ibat inhibitors, their uses, and pharmaceutical composition and combinations

专利摘要:
ibat inhibitors, their uses, and pharmaceutical composition and combinations the present invention relates to ibat specific inhibitors useful in the prophylaxis and / or treatment of a liver disease. it also refers to compositions comprising these ibat inhibitors, a method for the treatment of disorders and a set comprising substances or compositions.
公开号:BR112013010157B1
申请号:R112013010157
申请日:2011-11-08
公开日:2020-02-04
发明作者:Graffner Hans；Starke Ingemar；Gillberg Per-Göran
申请人:Albireo Ab；
IPC主号:

专利说明:

[0001] The ileal bile acid transporter (IBAT) is the main mechanism for the reabsorption of bile acids from the gastrointestinal tract. Partial or complete blockade of whose mechanism will result in the lowest concentration of bile acids in the wall of the small intestine, portal vein, liver parenchyma, intrahepatic biliary tree, extrahepatic biliary tree, including gallbladder.
[0002] The diseases that can benefit from partial or complete blockage of the IBAT mechanism may be that or having as a primary pathophysiological defect, causing or having symptoms of very high concentration of bile acids in the serum and organs above. WO 2008/058630 describes the effect of a certain ileal bile acid carrier (IBAT) in the treatment of liver disease related to fat disorders.
Summary of the Invention [0003] The present invention relates to specific inhibitors of
IBAT in the prophylaxis and / or treatment of liver disease. Detailed Description of the Invention [0004] The invention relates to the IBAT inhibitor compounds of the formula (I):
( ^Rz ) _v (I)
Petition 870190089048, of 09/09/2019, p. 12/161
2/70 where:
[0005] M is CH2, NH.
[0006] One of R ¹ and R ² is selected from hydrogen or C1-6 alkyl and the other is selected from C1-6 alkyl;
[0007] R ^x and R ^y are independently selected from hydrogen, hydroxy, amino, mercapto, C1-6 alkyl, C1-6 alkoxy, N- (C1-6 alkyl) amino, N, N- (C1- alkyl) 6) 2amino, C1-6S alkyl (0) a where a is 0 to 2 [0008] R ^z is selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1 alkyl -6, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkanoyl, C1-6 alkanoyloxy, N- (C1-6 alkyl) amino, N, N (C1-6 alkyl) 2amino, C1-6 alkanoylamino, N - (C1-6alkyl) carbamoyl, N, N (C1-6alkyl) 2carbamoyl, C1-6alkyl (O) a where a is 0 to 2, C1-6 alkoxycarbonyl, N- (C1-6alkyl) sulfamoyl and N, N- (C1-6alkyl) 2sulfamoyl; [0009] v is 0-5;
[00010] one of R4 and R ⁵ is a group of the formula (IA):
(IA) [00011] R3 and R ⁶ and the other from R4 and R ⁵ are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-4 alkyl, alkenyl C2-4, C2-4 alkynyl, C1-4 alkoxy, C1-4 alkanoyl, C1-4 alkanoyloxy, N- (C1- alkyl)
4) amino, N, N- (C1-4alkyl) 2amino, C1-4alkanoylamino, N- (C1-alkyl)
4) carbamoyl, N, N- (C1-4alkyl) 2carbamoyl, C1-4Salkyl (O) a where a is 0 to 2, C1-4 alkoxycarbonyl, N- (C1-4alkyl) sulfamoyl and N, N- (C14 alkyl) 2 sulfamoyl; wherein R3 and R ⁶ and the other of R ⁴ and R ⁵ can be optionally substituted on carbon by means of one or more of R ¹⁶ ;
Petition 870190089048, of 09/09/2019, p. 12/17
3/70 [00012] X is -O-, -N (R ^a ) -, -S (O) b- or -CH (R ^a ) -; where R ^a is hydrogen or C1-6 alkyl and b is 0-2;
[00013] Ring A is aryl or heteroaryl; wherein Ring A is optionally substituted by one or more substituents selected from R ¹⁷ ;
[00014] R ⁷ is hydrogen, C1-4alkyl, carbocyclyl or heterocyclyl; wherein R ⁷ is optionally substituted by one or more substituents selected from R ¹⁸ ;
[00015] R ⁸ is hydrogen or C1-4 alkyl;
[00016] R ⁹ is hydrogen or C1-4 alkyl;
[00017] R ¹⁰ is hydrogen, C1-4alkyl, carbocyclyl or heterocyclyl; wherein R ¹⁰ is optionally substituted by one or more substituents selected from R ¹⁹ ;
[00018] R ¹¹ is carboxy, sulpho, sulfine, phosphono, -P (O) (OR ^c ) (OR ^d ), P (O) (OH) (OR ^C ), -P (O) (OH) (R ^d ) or -P (O) (OR ^c ) (R ^d ) where R ^c and R ^d are independently selected from C 1-6 alkyl; or R ¹¹ is a group of the formula (IB) or (IC):
(IB) (IC) where:
[00019] 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-; where a is 0-2, v is 1-2, R ^s and R ^f are independently selected from hydrogen or C 1-4 alkyl optionally substituted by R ²⁶ and R ⁿ is hydrogen or C 1-4 alkyl;
[00020] R ¹² is hydrogen or C1-4 alkyl;
[00021] R ¹³ and R ¹⁴ are independently selected from hydrogen, C 1-4 alkyl, carbocyclyl or heterocyclyl; and when q is 0,
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4/70
R ¹⁴ can additionally be selected from hydroxy where R ¹³ and R ¹⁴ can independently be optionally substituted by one or more substituents selected from R ²⁰ ;
[00022] R ¹⁵ is carboxy, sulpho, sulfine, phosphono, -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 C1-6 alkyl;
[00023] p is 1-3; wherein the values of R ¹³ can be the same or different;
[00024] q is 0-1;
[00025] r is 0-3; wherein the values of R ¹⁴ can be the same or different;
[00026] m is 0-2; wherein the values of R ¹⁰ can be the same or different;
[00027] n is 1-3; wherein the values of R ⁷ can be the same or different;
[00028] Ring B is a nitrogen-bonded heterocyclyl substituted on carbon by a group selected from R ²³ , and optionally additionally substituted on carbon by one or more of R ²⁴ ; and wherein if said nitrogen-bound heterocyclyl contains a portion of -NH-, that nitrogen can be optionally substituted by a group selected from R ²⁵ ;
[00029] R ¹⁶ , R ¹⁷ and R ¹⁸ are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C14 alkanoyl, C1-4 alkanoyloxy, ^ - (C1-4 alkyl) amino, M, M- (C1-4 alkyl, C1-4 alkanoylamino, ^ - (C1-4 alkyl) carbamoyl, M, M- (C1 alkyl carbamoyl, C1-4 alkyl (O) a where a is 0 to 2, C1-4 alkoxycarbonyl, ^ - (C14 alkyl) sulfamoyl and M, M- (C1-4 alkyl) 2 sulfamoyl wherein R ¹⁶ , R ¹⁷ and R ¹⁸ can be independently optionally substituted on carbon by means of one or more of R ²¹ ;
Petition 870190089048, of 09/09/2019, p. 12/191
5/70 [00030] R ¹⁹ , R ²⁰ , R ²⁴ and R ²⁶ are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-4 alkyl, C2-4 alkenyl , C2-4 alkynyl, C1-4 alkoxy, C1-4 alkanoyl, C1-4 alkanoyloxy, ^ - (C1-4 alkyl) amino, M, M- (C ^ amino alkyl, C1-4 alkanoylamino, ^ - (alkyl C1-4) carbamoyl, M, M- (C14 alkyl) 2 carbamoyl, C1-4 alkyl (O) a where a is 0 to 2, C1-4 alkoxycarbonyl, M- (C1-4 alkyl) sulfamoyl, M, M- (C ^ alkyl sulfamoyl, carbocyclyl, heterocyclyl, benzyloxycarbonylamino, sulfo, sulfine, amidino, phosphono, P (O) (OR ^a ) (OR ^b ), -P (O) (OH) (OR ^a ), -P (O) (OH) (R ^a ) or -P (O) (OR ^a ) (R ^b ), where R ^a and R ^b are independently selected from C1-6 alkyl; where R ¹⁹ , R ²⁰ , R ²⁴ and R ²⁶ can independently be optionally substituted on carbon by means of one or more of R ²² ;
[00031] R ²¹ and R ²² are independently selected from halo, hydroxy, cyano, carbamoyl, ureide, amino, nitro, carboxy, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, ally, ethynyl, methoxycarbonyl, formyl, acetyl, formamide, acetylamino, acetoxy, methylamino, dimethylamino, Nmethylcarbamoyl, Μ, Μ-dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl and M, M-dimethyl;
[00032] R ²³ is carboxy, sulpho, sulfine, phosphono, -P (O) (OR ^g ) (OR ^h ), P (O) (OH) (OR ^g ), -P (O) (OH) (R ^g ) or -P (O) (OR ^g ) (R ^h ) where R ^g and R ^h are independently selected from C1-6 alkyl;
[00033] R ²⁵ is selected from C1-6 alkyl, C1-6 alkanoyl, C1-6 alkylsulfonyl, C1-6 alkoxycarbonyl, carbamoyl, ^ - (C1-6 alkyl) carbamoyl, M, M- (C1- alkyl) 6) carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulfonyl;
[00034] or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof for use in the prophylaxis or treatment of a liver disease.
[00035] The compounds as employed according to the invention
Petition 870190089048, of 09/09/2019, p. 12/20
6/70 tion improve liver tests (serum amino transferases) and liver histology and significantly reduce the hydroxyproline content and the number of infiltrating neutrophils and proliferation of hepatocytes and cholangiocytes.
[00036] In the literature, IBAT inhibitors are often referred to by different names. It is to be understood that where IBAT inhibitors are referred to here, this term also encompasses compounds known in the literature as: i) ileal apical sodium codependent bile acid transporter (ASBT) inhibitors; ii) bile acid transporter (BAT) inhibitors; iii) bile acid / ileal sodium cotransporter system inhibitors; iv) apical bile-sodium acid cotransporter inhibitors; v) ileal sodium-dependent bile acid transporter inhibitors; vi) bile acid reabsorption inhibitors (BARI's); and vii) sodium bile acid transporter (SBAT) inhibitors; where they act through IBAT inhibition.
[00037] In this specification the term alkyl includes both straight and branched chain alkyl groups, but references to the individual alkyl groups, such as propyl, are specific to the straight chain version only. For example, C1-6 alkyl includes C1-4 alkyl, C1-3 alkyl, propyl, isopropyl and f-butyl. In any case, references to individual alkyl groups, such as 'propyl' are specific to the straight chain version only and references to individual branched chain alkyl groups, such as 'isopropyl' are specific to the branched chain version only. A similar convention applies to other radicals, for example, C1-6 alkyl phenyl would include C1-4 alkyl phenyl, benzyl, 1-phenylethyl and 2-phenylethyl. The term halo refers to fluorine, chlorine, bromine and iodine.
[00038] Where optional substituents are chosen from
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7/70 one or more groups is to be understood that this definition includes all substituents to be chosen from one of the specific groups or the substituents to be chosen from two or more of the specific groups.
[00039] Heteroaryl is a mono or bicyclic ring, totally unsaturated containing 3 to 12 atoms of which at least one atom is chosen from nitrogen, sulfur or oxygen, which can, unless otherwise specified, be linked by nitrogen or carbon. Preferably heteroaryl refers to a monocyclic ring, completely unsaturated, containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms of which at least one atom is chosen from nitrogen, sulfur or oxygen, which can, unless otherwise specified, be bound by nitrogen or carbon. In another aspect of the invention, heteroaryl refers to a monocyclic ring, completely unsaturated, containing 5 or 6 atoms or a bicyclic ring containing 8, 9 or 10 atoms of which at least one atom is chosen from nitrogen, sulfur or oxygen, which can, unless otherwise specified, be linked by nitrogen or carbon. Examples and suitable values of the term heteroaryl are thienyl, isoxazolyl, imidazolyl, pyrrolyl, thiadiazolyl, isothiazolyl, triazolyl, pyranyl, indolyl, pyrimidyl, pyrazinyl, pyridazinyl, pyridyl and quinolyl. Preferably, the term heteroaryl refers to thienyl or indolyl.
[00040] Arila is a mono or bicyclic carbon ring totally unsaturated, containing from 3 to 12 atoms. Preferably aryl is a monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms. Suitable values for aryl include phenyl or naphthyl. Particularly aryl is phenyl.
[00041] A heterocyclyl is a saturated mono or bicyclic ring, partially saturated or unsaturated, containing 3 to 12 atoms of which at least one atom is chosen from nitrogen, sulfur
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8/70 or oxygen, which can, unless otherwise specified, be linked by nitrogen or carbon, where a -CH2- group can optionally be replaced by a -C (O) - or a sulfur atom ring can optionally be oxidized to form S oxides. Preferably heterocyclyl is a saturated, partially saturated or unsaturated mono or bicyclic ring, containing 5 or 6 atoms of which at least one atom is chosen from nitrogen, sulfur or oxygen, which can, unless otherwise specified, be linked by nitrogen or carbon, where a group of -CH2- can optionally be replaced by a -C (O) - or a sulfur atom ring can be optionally oxidized to form the oxide (s) of S. Examples and suitable values of the term heterocyclyl are thiazolidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2,5-dioxopyrrolidinyl, 2-benzoxazolinonyl, 1,1-dioxotetrahydrothienyl, 2,4dioxoimidazolidinyl , 2-oxo-1,3,4- (4-triazole 2-oxazolidinonyl, 5,6-dihydrouracilyl, 1,3-benzodioxolyl, 1,2,4-oxadiazolyl, 2-azabicyclo [2.2.1] heptyla, 4-thiazolidonyl, morpholine, 2-oxotetrahydrofuranyl, tetrahydrofuranyl, 2 , 3-dihydrobenzofuranyl, benzothienyl, tetrahydropyranyl, piperidyl, 1-oxo-1,3-dihydroisoindolyl, piperazinyl, thiomorpholino, 1,1-dioxothiomorpholino, tetrahydropyranyl, 1,3-dioxolanil, homopiperazinyl, thienyl, thienyl , imidazolyl, pyrrolyl, thiadiazolyl, isothiazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, pyranyl, indolyl, pyrimidyl, thiazolyl, pyrazinyl, pyridazinyl, pyridyl, 4-pyridonyl, quinolyl and 1isoquinolonyl.
[00042] A carbocyclyl is a saturated, partially saturated or unsaturated mono or bicyclic carbon ring, containing 3 to 12 atoms; wherein a group of -CH2- can optionally be replaced by a -C (O) -. Preferably, carbocyclyl is a monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms. Suitable values for carbocyclyl include cyclopropyl,
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9/70 cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl, tetralinyl, indanyl or 1-oxoindanyl. Particularly carbocyclyl is cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl or 1oxoindanyl.
[00043] In example C1-6 alkanoyloxy and C1-4 alkanoyloxy is acetoxy. Examples of C1-6 alkoxycarbonyl and C1-4 alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, n- and i-butoxycarbonyl. Examples of C1-6 alkoxy and C1-4 alkoxy include methoxy, ethoxy and propoxy. Examples of C1-6 alkanoylamino and C1-4 alkanoylamino include formamide, acetamido and propionylamino. Examples of C16S alkyl (O) a where a is 0 to 2 and C1-4 alkyl (O) a where a is 0 to 2 include methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl and ethylsulfonyl. Examples of C1-6 alkanoyl and C1-4 alkanoyl include C1-3 alkanoyl, propionyl and acetyl. Examples of N- (C1-6alkyl) amino and N- (C1-4alkyl) amino include methylamino and ethylamino. Examples of N, N (C1-6alkyl) 2amino and N, N- (C1-4alkyl) 2amino include di-N-methylamino, di- (N-ethyl) amino and N-ethyl-N-methylamino. Examples of C2-6 alkenyl and C2-4 alkenyl are vinyl, allyl and 1-propenyl. Examples of C2-6 alkynyl and C2-4 alkynyl are ethynyl, 1-propynyl and 2-propynyl. Examples of N- (C1-6alkyl) sulfamoyl and N- (C1-4alkyl) sulfamoyl are N- (C1-3alkyl) sulfamoyl, N- (methyl) sulfamoyl and N- (ethyl) sulfamoyl. Examples of N- (C1-6alkyl) 2sulfamoyl and N-4) 2sulfamoyl are N, N (dimethyl) sulfamoyl and N- (methyl) -N- (ethyl) sulfamoyl. Examples of N (C 1-6 alkyl) carbamoyl and N- (C 1-4 alkyl) carbamoyl are methylaminocarbonyl and ethylaminocarbonyl. Examples of N, N- (C16 alkyl) 2-carbamoyl and N, N- (C1-4 alkyl) 2-carbamoyl are dimethylaminocarbonyl and methylethylaminocarbonyl. Examples of C1-6 alkoxycarbonylamino are ethoxycarbonylamino and i-butoxycarbonylamino. Examples of N '- (C 1-6 alkyl) ureido are N'-methylureido and N'-ethylureido. The examples
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10/70 of N- (C1-6 alkyl) ureido are N-methylureido and N-ethylureido. Examples of N ', N' - (C1-6alkyl) 2ureido are N ', N'-dimethylureido and N'-methyl-N'ethylureido. Examples of N '- (C1-6 alkyl) -N- (C1-6 alkyl) ureido are N'methyl-N-methylureido and N'-propyl-N-methylureido. Examples of N ', N' (C1-6 alkyl) 2-N- (C1-6 alkyl) ureido are N ', N'-dimethyl-N-methylureido and N'methyl-N'-ethyl-N-propylureido .
[00044] A suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid addition salt of a compound of the invention that is sufficiently basic, for example, an acid addition salt with, for example, an acid organic or inorganic, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, citric or maleic acid.
[00045] In addition, a suitable pharmaceutically acceptable salt of a compound of the invention that is sufficiently acidic is an alkali metal salt, for example, a potassium or sodium salt, an alkaline earth metal salt, for example, a salt of magnesium or calcium, an ammonium salt or a salt with an organic base that offers a physiologically acceptable cation, for example, a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris- (2-hydroxyethyl) amine.
[00046] The compounds of formula (I) can be administered in the form of a prodrug that is divided into the human or animal body to produce a compound of formula (I).
[00047] Examples of prodrugs include in vivo hydrolysable esters and in vivo hydrolysable amides of a compound of formula (I).
[00048] An in vivo hydrolyzable ester of a compound of formula (I) containing a hydroxy or carboxy group is, for example, a pharmaceutically acceptable ester that is hydrolyzed in the human or animal body to produce the alcohol or acid source. Suitable pharmaceutically acceptable esters for the carboxy include the alkoxy esters
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11/70 C1-6 methyl, for example, methoxymethyl, C1-6 alkanoyloxymethyl esters, for example, pivaloyloxymethyl, phthalidyl esters, C1-6 cycloalkoxycarbonyloxy C1-6 alkyl esters, for example, 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters, for example, 5-methyl-1,3-dioxolen-2onylmethyl; and C 1-6 alkoxycarbonyloxyethyl esters, for example, 1-methoxy-carbonyloxyethyl and can be formed on any carboxy group in the compounds of this invention.
[00049] An in vivo hydrolyzable ester of a compound of formula (I) containing a hydroxy group includes inorganic esters, such as phosphate esters and α-acyloxyalkyl ethers and related compounds which as a result of in vivo hydrolysis of the ester breaking down to produce the parent hydroxy group. Examples of αacyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy. A selection of hydrolyzable ester forming groups in vivo for hydroxy includes alkanoyl, benzoyl, phenylacetyl and phenylacetyl and substituted benzoyl, alkoxycarbonyl (to produce the alkyl carbonate esters), dialkylcarbamoyl and N (dialkylaminoethyl) -N-alkylcarbamoyl (para-alkylcarbamoyl). ), dialkylaminoacetyl and carboxyacetyl. Examples of substituents on the benzoyl include morpholino and piperazine attached from a nitrogen atom ring through a methylene group to the 3- or 4- position of the benzoyl ring.
[00050] A suitable value for an in vivo hydrolyzable amide of a compound of formula (I) containing a carboxy group is, for example, an N-C1-6 alkyl or N, N-di-C1-6 alkyl amide , such as, Nmethyl, N-ethyl, N-propyl, N, N-dimethyl, N-ethyl-N-methyl or N, Ndiethyl amide. It is also to be understood that certain compounds of the formula (I) can exist in the solvated as well as unsolvated forms, such as, for example, hydrated forms. It is to be understood that the invention covers all such forms of solvate that have IBAT inhibitory activity.
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12/70 [00051] Preferred values for R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as follows. Such amounts may be used where appropriate with any of the definitions, claims or modalities defined hereinbefore or hereinafter.
[00052] Preferably R ¹ and R ² are independently selected from C 1-4 alkyl.
[00053] More preferably R ¹ and R ² are independently selected from ethyl or butyl.
[00054] More preferably R ¹ and R ² are independently selected from ethyl, propyl or butyl.
[00055] In one aspect of the invention particularly R ¹ and R ² are both butyl.
[00056] In another aspect of the invention particularly R ¹ and R ² are both propyl.
[00057] In another aspect of the invention particularly one of R ¹ and R ² is ethyl and the other is butyl.
[00058] Preferably R ^x and R ^y are independently selected from hydrogen or C1-6 alkyl.
[00059] Most preferably R ^x and R ^y are both hydrogen.
[00060] Preferably R ^z is selected from halo, amino, C1-6 alkyl, C1-6 alkoxycarbonylamino or M '- (C1-6 alkyl) ureido.
[00061] More preferably R ^z is selected from chlorine, amino, f-butyl, f-butoxycarbonylamino or ^ '- (C1-6alkyl) ureido.
[00062] Preferably v is 0 or 1.
[00063] In one aspect of the invention, more preferably v is 0.
[00064] In one aspect of the invention, more preferably v is 1.
[00065] In one aspect of the invention preferably R ⁴ is a group of the formula (IA) (as described above). In another aspect of the invention preferably R ⁵ is a group of the formula (IA) (as described above). [00066] Preferably R ³ and R ⁶ are hydrogen.
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13/70 [00067] Preferably the other of R ⁴ and R ⁵ which is not the group of the formula (IA) is selected from halo, C1-4 alkoxy or C14S alkyl (0) a where a is 0 to 2; wherein R ⁴ or R ⁵ can be optionally substituted on carbon by means of one or more of R ¹⁶ ; wherein R ¹⁶ is independently selected from hydroxy and N, N- (C14 alkyl) 2amino.
[00068] More preferably the other of R ⁴ and R ⁵ which is not the group of the formula (IA) is selected from bromine, methoxy, isopropoxy, methylthio, ethylthio, isopropylthio or mesyl; wherein R ⁴ or R ⁵ can be optionally substituted on carbon by means of one or more of R ¹⁶ ; where R ¹⁶ is independently selected from hydroxy and N, Ndimethylamino.
[00069] Particularly the other of R ⁴ and R ⁵ that is not the group of formula (IA) is selected from bromine, methoxy, isopropoxy, methylthio, ethylthio, isopropylthio, 2-hydroxyethylthio, 2- (N, N- dimethylamino) ethylthio or mesyl.
[00070] More particularly the other of R ⁴ and R ⁵ which is not the group of the formula (IA) is methylthio. Preferably the other of R ⁴ and R ⁵ which is not the group of the formula (IA) is selected from hydrogen, halo, C 1-4 alkoxy or C 1-4 alkyl (0) a where a is 0 to 2 ; wherein R ⁴ or R ⁵ can be optionally substituted on carbon by means of one or more of R ¹⁶ ; wherein R ¹⁶ is independently selected from hydroxy, carboxy and N, N- (C 1 amino).
[00071] More preferably the other of R ⁴ and R ⁵ which is not the group of the formula (IA) is selected from hydrogen, bromine, methoxy, isopropoxy, methylthio, ethylthio, isopropylthio or mesyl; wherein R ⁴ or R ⁵ can be optionally substituted on carbon by means of one or more of R ¹⁶ ; wherein R ¹⁶ is independently selected from hydroxy, carboxy and N, N-dimethylamino.
[00072] Particularly the other of R ⁴ and R ⁵ that is not the group of
Petition 870190089048, of 09/09/2019, p. 12/28
14/70 formula (IA) is selected from hydrogen, bromine, methoxy, isopropoxy, methylthio, carboxymethylthio, ethylthio, isopropylthio, 2-hydroxyethylthio, 2 (N, N-dimethylamino) ethylthio or mesyl. In another aspect of the invention, more preferably the other of R ⁴ and R5 which is not the group of the formula (IA) is selected from hydrogen, chlorine, bromine, methoxy, isopropoxy, methyl, ethyl, or isopropylthio; wherein R ⁴ or R ⁵ can be optionally substituted on carbon by means of one or more of R ¹⁶ ; wherein R ¹⁶ is independently selected from hydroxy, carboxy and M, M-dimethylamino.
[00073] In another aspect of the invention, particularly the other of R ⁴ and R5 which is not the group of the formula (IA) is selected from hydrogen, chlorine, bromine, methoxy, isopropoxy, methylthio, carboxymethylthio, ethylthio, isopropylthio, 2-hydroxyethylthio or 2- (M, M-dimethylamino) ethylthio.
[00074] In another aspect of the invention, more particularly the other of R ⁴ and R5 which is not the group of the formula (IA) is bromine or chlorine.
[00075] In another aspect of the invention, more particularly the other of R ⁴ and R5 which is not the group of the formula (IA) is methoxy.
[00076] In one aspect of the invention, preferably Ring A is aryl.
[00077] In another aspect of the invention, preferably Ring A is heteroaryl.
[00078] When Ring A is aryl, preferably Ring A is phenyl. [00079] When Ring A is heteroaryl, Ring A is preferably thienyl or indolyl.
[00080] Preferably Ring A is aryl or heteroaryl; wherein Ring A is optionally substituted by one or more substituents selected from R ¹⁷ ; wherein R ¹⁷ is selected from halo, hydroxy or C 1-4 alkyl; wherein R ¹⁷ can be optionally substituted on carbon by means of one or more of R ²¹ ; where R ²¹ is selected from the halo.
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15/70 [00081] Preferably X is -O.
[00082] More preferably Ring A is phenyl, thienyl or indolyl; wherein Ring A is optionally substituted by one or more substituents selected from halo, hydroxy or trifluoromethyl.
[00083] Particularly Ring A is selected from phenyl, 4-hydroxyphenyl, thien-2-yl, 4-trifluoromethylphenyl, 3-hydroxyphenyl, 2-fluorophenyl, 2,3-dihydroxyphenyl or indol-3-yl. More particularly, ring A is phenyl.
[00084] In another aspect of the invention, preferably Ring A is aryl or heteroaryl; wherein Ring A is optionally substituted by one or more substituents selected from R ¹⁷ ; wherein R ¹⁷ is selected from halo, hydroxy, C 1-4 alkyl or C 1-4 alkoxy; wherein R ¹⁷ can be optionally substituted on carbon by means of one or more of R ²¹ ; where R ²¹ is selected from the halo.
[00085] In another aspect of the invention, more preferably the ring
A is phenyl, thienyl or indolyl; wherein Ring A is optionally substituted by one or more substituents selected from halo, hydroxy, methoxy or trifluoromethyl.
[00086] In another aspect of the invention, particularly Ring A is selected from phenyl, 4-hydroxyphenyl, 4-methoxyphenyl, thien-2-yl, 4-trifluoromethylphenyl, 3-hydroxyphenyl, 2-fluorophenyl, 2,3- dihydroxyphenyl or indol-3-yl.
[00087] In another aspect of the invention, particularly Ring A is selected from phenyl, 4-hydroxyphenyl, 4-methoxyphenyl, thien-2yl, 4-trifluoromethylphenyl, 3-hydroxyphenyl, 2-fluorophenyl, 4-fluorophenyl, 2 , 3-dihydroxyphenyl or indol-3-yl.
[00088] Preferably R ⁷ is hydrogen, C1-4 alkyl or carbocyclyl.
[00089] More preferably R ⁷ is hydrogen, methyl or phenyl.
[00090] Particularly R ⁷ is hydrogen.
[00091] In one aspect of the invention, preferably R ⁸ is hydrogenPetition 870190089048, 09/09/2019, pg. 12/30
16/70 nio.
[00092] In another aspect of the invention, preferably R ⁸ is C 1-4 alkyl.
[00093] In another aspect of the invention, more preferably R ⁸ is hydrogen or methyl.
[00094] In one aspect of the invention, preferably R ⁹ is hydrogen.
[00095] In another aspect of the invention, preferably R ⁹ is alkyl
C1-4.
[00096] In another aspect of the invention, more preferably R ⁹ is hydrogen or methyl.
[00097] Preferably R ¹⁰ is hydrogen.
[00098] In one aspect of the invention, preferably R ¹¹ is carboxy, sulfo, sulfine, phosphono, -P (O) (OR ^c ) (OR ^d ), -P (O) (OH) (OR ^c ), P (O) (OH) (R ^d ) or -P (O) (OR ^c ) (R ^d ) where R ^c and R ^d are independently selected from C1-6 alkyl.
[00099] In another aspect of the invention, preferably R11 is a group of the formula (IB) (as described above).
[000100] Preferably R ¹¹ is carboxy, -P (O) (OH) (OR ^c ) or a group of the formula (IB) (as described above). More preferably R ¹¹ is carboxy, -P (O) (OH) (OEt) or a group of the formula (IB) (as described above).
[000101] In another aspect of the invention, preferably R ¹¹ is carboxy, sulfo, -P (O) (OH) (OR ^c ) where R ^c is selected from C14 alkyl or a group of the formula (IB) ( as described above).
[000102] Preferably Y is -NH- or -NHC (O) -.
[000103] More preferably Y is -NHC (O) -.
[000104] In one aspect of the invention, preferably R ¹² is hydrogen.
[000105] In another aspect of the invention, preferably R ¹² is alkyl
Petition 870190089048, of 09/09/2019, p. 12/31
17/70
Ci-4.
[000106] In another aspect of the invention, more preferably R ¹² is hydrogen or methyl.
[000107] Preferably R ¹³ is hydrogen, C1-4 alkyl or carbocyclyl; wherein R ¹³ is optionally substituted by one or more substituents selected from R ²⁰ ; where R ²⁰ is hydroxy.
[000108] More preferably R ¹³ is hydrogen, methyl or phenyl; wherein R ¹³ is optionally substituted by one or more substituents selected from R ²⁰ ; where R ²⁰ is hydroxy.
[000109] Particularly R ¹³ is hydrogen, hydroxymethyl or phenyl. [000110] More particularly R ¹³ is hydrogen or hydroxymethyl.
[000111] In another aspect of the invention, preferably ^R13 is hydrogen, C1-4 alkyl or carbocyclyl; wherein R ¹³ is optionally substituted by one or more substituents selected from R ²⁰ ; wherein R ²⁰ is hydroxy, carboxy, carbocyclyl or amino; wherein R ²⁰ can be optionally substituted on carbon by means of one or more of R ²² ; R ²² is hydroxy.
[000112] In another aspect of the invention, more preferably R ¹³ is hydrogen, methyl, ethyl, butyl or phenyl; wherein R ¹³ is optionally substituted by one or more substituents selected from R ²⁰ ; wherein R ²⁰ is hydroxy, carboxy, phenyl or amino; wherein R ²⁰ can be optionally substituted on carbon by means of one or more of R ²² ; R ²² is hydroxy.
[000113] In another aspect of the invention, particularly R ¹³ is hydrogen, hydroxymethyl, 4-aminobutyl, 2-carboxyethyl, 4-hydroxybenzyl or phenyl.
[000114] In another aspect of the invention, preferably R ¹³ is hydrogen, C1-4 alkyl or carbocyclyl; wherein R ¹³ is optionally substituted by one or more substituents selected from R ²⁰ ; wherein R ²⁰ is hydroxy, carboxy, carbocyclyl, heterocyclyl or amino; on what
Petition 870190089048, of 09/09/2019, p. 12/31
18/70
R ²⁰ can be optionally substituted on carbon by means of one or more of R ²² ; R ²² is hydroxy.
[000115] In another aspect of the invention, more preferably R ¹³ is hydrogen, methyl, ethyl, butyl or phenyl; wherein R ¹³ is optionally substituted by one or more substituents selected from R ²⁰ ; wherein R ²⁰ is hydroxy, carboxy, phenyl, imidazolyl or amino; wherein R ²⁰ can be optionally substituted on carbon by means of one or more of R ²² ; R ²² is hydroxy.
[000116] In another aspect of the invention, particularly R ¹³ is hydrogen, hydroxymethyl, 4-aminobutyl, 2-carboxyethyl, 4hydroxybenzyl, imidazole-5-ylmethyl or phenyl.
[000117] In yet another aspect of the invention, preferably R ¹³ is hydrogen, C 1-4 alkyl, carbocyclyl or R ²³ ; wherein R ¹³ is optionally substituted by one or more substituents selected from R ²⁰ ; wherein R ²⁰ is hydroxy, C 1-4 alkyl (O) one where one is 0, C 1-4 alkoxy, amino, carbocyclyl, heterocyclyl or mercapto; wherein R ²⁰ can independently be optionally substituted on carbon by means of one or more of R ²² ; R ²² is selected from hydroxy; and R ²³ is carboxy.
[000118] In yet another aspect of the invention, more preferably R ¹³ is hydrogen, methyl, ethyl, butyl or phenyl or R ²³ ; wherein 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; wherein R ²⁰ can independently be optionally substituted on carbon by means of one or more of R ²² ; R ²² is selected from hydroxy; and R ²³ is carboxy.
[000119] In yet another aspect of the invention, particularly R ¹³ is hydrogen, carboxy, hydroxymethyl, mercaptomethyl, methoxymethyl, methylthiomethyl, 2-methylthioethyl, 4-aminobutyl, 4-hydroxybenzyl, imidazole-5ylmethyl or phenyl.
Petition 870190089048, of 09/09/2019, p. 12/31
19/70 [000120] In another aspect more particularly R ¹³ is methylthiomethyl, methylsulfinylmethyl or methylsulfonylmethyl.
[000121] Preferably R ¹⁴ is hydrogen.
[000122] In another aspect of the invention, preferably R ¹⁴ is selected from hydrogen, C 1-4 alkyl or carbocyclyl; wherein said C 1-4 alkyl or carbocyclyl can optionally be substituted by one or more substituents selected from R ²⁰ ; and R ²⁰ is hydroxy.
[000123] 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.
[000124] In another aspect of the invention, particularly R ¹⁴ is hydrogen, phenyl or hydroxymethyl. Particularly R ¹⁵ is carboxy or sulfo.
[000125] In one aspect of the invention, more particularly R ¹⁵ is carboxy.
[000126] In another aspect of the invention, more particularly R ¹⁵ is sulfo.
[000127] 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 C1-4 alkyl.
[000128] 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.
[000129] Preferably R ¹⁵ is carboxy, sulfo, -P (O) (OEt) (OEt), P (O) (OH) (OEt), -P (O) (OH) (Me) or -P ( O) (OEt) (Me).
[000130] 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 ) where R ^e and R ^f are independently selected from C 1-4 alkyl or R ¹⁵ is a group of the formula (IC) (as described above).
Petition 870190089048, of 09/09/2019, p. 12/31
20/70 [000131] 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 ) where R ^e and R ^f are independently selected from methyl or ethyl or R ¹⁵ is a group of the formula (IC) (as described above).
[000132] Preferably R ¹⁵ is carboxy, sulfo, phosphono, P (O) (OEt) (OEt), -P (O) (Of-Bu) (Of-Bu), -P (O) (OH) ( OEt), -P (O) (OH) (Me) or -P (O) (OEt) (Me) or R ¹⁵ is a group of the formula (IC) (as described above).
[000133] In one aspect of the invention, preferably R ¹⁵ is carboxy. [000134] In another aspect of the invention, preferably R ¹⁵ is sulfo.
[000135] In another aspect of the invention, preferably R ¹⁵ is P (O) (OH) (OEt).
[000136] In another aspect of the invention, preferably R ¹⁵ is P (O) (OH) (Me).
[000137] In another aspect of the invention, preferably R ¹⁵ is P (O) (OEt) (Me).
[000138] nio. In one aspect of the invention, preferably R ²⁴ is hydrogen [000139]Λ In another aspect of the invention, preferably R ²⁴ is alkyl C1-4.[000140][000141][000142] Preferably R ²⁵ is hydrogen. Preferably R ²⁶ is carboxy. Preferably p is 1 or 2; where the values of R ¹³ can
be the same or different.
[000143] In one aspect of the invention, more preferably p is 1.
[000144] In another aspect of the invention, more preferably p is 2;
wherein the values of R ¹³ can be the same or different.
[000145] In another aspect of the invention, more preferably p is 3; wherein the values of R ¹³ can be the same or different.
[000146] In one aspect of the invention, preferably q is 0.
Petition 870190089048, of 09/09/2019, p. 12/35
21/70 [000147] In another aspect of the invention, preferably q is 1.
[000148] In one aspect of the invention, preferably r is 0.
[000149] In one aspect of the invention, more preferably r is 1.
[000150] In another aspect of the invention, more preferably r is 2;
wherein the values of R ¹⁴ can be the same or different.
[000151] In another aspect of the invention, more preferably r is 3; wherein the values of R ¹⁴ can be the same or different. [000152] Preferably m is 0.
[000153] In another aspect of the invention, preferably m is 0 or 1.
[000154] Preferably n is 1.
[000155] In another aspect of the invention, preferably n is 1 or 2.
[000156] Preferably z is 1.
[000157] The group of the formula (IA) in which R ⁷ is hydrogen, methyl or phenyl, n is 1, Ring A is phenyl, thienyl or indolyl; wherein Ring A is optionally substituted by one or more substituents selected from halo, hydroxy or trifluoromethyl, m is 0 and R ⁹ is carboxy, P (O) (OH) (OR ^c ) or a group of the formula (IB ).
[000158] The group of the formula (IA) where: X is -0-.
[000159] Ring A is phenyl, thienyl or indolyl; wherein Ring A is optionally substituted by one or more substituents selected from halo, hydroxy, methoxy or trifluoromethyl;
[000160] R ⁷ is hydrogen, methyl or phenyl;
[000161] R ⁸ is hydrogen or methyl;
[000162] R ⁹ is hydrogen or methyl;
[000163] R ¹⁰ is hydrogen;
[000164] m is 0-2 where the values of R ¹⁰ can be the same or different; and R ¹¹ is carboxy, -P (O) (OH) (OEt) or a group of the formula (IB) (as described in claim 1); The group of the formula (IB) where R ¹⁰ is hydrogen, hydroxymethyl or phenyl, p is 1 or 2; where the values of R ¹⁰ can be the same or different and R ¹¹ is carboxy or
Petition 870190089048, of 09/09/2019, p. 12/36
22/70 sulfo.
[000165] The group of the formula (IB) where:
[000166] R ¹² is hydrogen or methyl;
[000167] R ¹³ is hydrogen, methyl, ethyl, butyl or phenyl or R ²³ ; wherein R ¹³ is optionally substituted by one or more substituents selected from R ²⁰ ; R ²⁰ is hydroxy, methylthio, methoxy, amino, imidazolyl or mercapto; wherein R ²⁰ can independently be optionally substituted on carbon by means of 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 can be optionally substituted by one or more substituents selected from hydroxy; 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 the formula (IC) (as described in claim 1);
[000168] p is 1 -3 where the values of R ¹³ can be the same or different;
[000169] q is 0-1; and [000170] r is 0-3 where the values of R ¹⁴ can be the same or different;
[000171] The group of the formula (IC) where [000172] R ²⁴ is hydrogen;
[000173] R ²⁵ is hydrogen;
[000174] R ²⁶ is carboxy; and [000175] z is 1;
[000176] or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
[000177] Therefore in another aspect of the invention, at this point a compound of formula (I) is produced as described above in which:
Petition 870190089048, of 09/09/2019, p. 37/121
23/70 [000178] R ¹ and R ² are independently selected from ethyl or butyl;
[000179] R ³ and R6 are hydrogen;
[000180] R4 is selected from halo, C1-4 alkoxy or C14S (O) alkyl a where a is 0 to 2; wherein R ⁴ can be optionally substituted on carbon by means of one or more of R ¹⁶ ; wherein R ¹⁶ is independently selected from hydroxy and M, M- (C14 alkyl) 2amino;
[000181] R5 is a group of the formula (IA);
[000182] Ring A is aryl or heteroaryl; wherein Ring A is optionally substituted by one or more substituents selected from R ¹⁷ ; where [000183] R ¹⁷ is selected from halo, hydroxy or C 1-4 alkyl; wherein R ¹⁷ can be optionally substituted on carbon by means of one or more of R ²¹ ; where [000184] R ²¹ is selected from the halo;
[000185] R ⁷ is hydrogen, C1-4alkyl or carbocyclyl;
[000186] R ¹¹ is carboxy, -P (O) (OH) (OR ^c ) or a group of the formula (IB) (as described above);
[000187] R ¹³ is hydrogen, C1-4alkyl or carbocyclyl; wherein R ¹³ is optionally substituted by one or more substituents selected from R ²⁰ ; where [000188] R ²⁰ is hydroxy;
[000189] R ¹⁵ is carboxy or sulfo;
[000190] p is 1 or 2; wherein the values of R ¹³ can be the same or different;
[000191] m is 0; and [000192] n is 1;
[000193] or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
Petition 870190089048, of 09/09/2019, p. 12/38
24/70 [000194] Therefore in a further aspect of the invention, at this point a compound of formula (I) is produced as described above where:
[000195] R ¹ and R ² are both butyl or one out of R ¹ and R ² is ethyl and the other is butyl;
[000196] R ⁴ is methylthio;
[000197] R ⁵ is a group of the formula (IA) (as described above);
[000198] R3 and R ⁶ are hydrogen;
[000199] Ring A is phenyl;
[000200] R ⁷ is hydrogen;
[000201] R ¹¹ is a group of the formula (IB) (as described above);
[000202] R ¹³ is hydrogen or hydroxymethyl;
[000203] R ¹⁵ is carboxy or sulfo;
[000204] p is 1 or 2; wherein the values of R ¹³ can be the same or different;
[000205] m is 0;
[000206] n is 1;
[000207] or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
[000208] Therefore in a further aspect of the invention, at this point a compound of formula (I) is produced as described above in which:
[000209] R ¹ and R ² are independently selected from ethyl or butyl;
[000210] R ³ and R ⁶ are hydrogen;
[000211] R ⁴ is selected from halo, C1-4 alkoxy or C14S alkyl (O) a where a is 0 to 2; wherein R ⁴ can be optionally substituted on carbon by means of one or more of R ¹⁶ ; wherein R ¹⁶ is independently selected from hydroxy and V, V- (C14 alkyl) 2amino;
Petition 870190089048, of 09/09/2019, p. 12/31
25/70 [000212] R ⁵ is a group of the formula (IA);
[000213] Ring A is aryl or heteroaryl; wherein Ring A is optionally substituted by one or more substituents selected from R ¹⁷ ;
[000214] R ⁷ is hydrogen, C1-4alkyl or carbocyclyl;
[000215] R8 is hydrogen or methyl;
[000216] R9 is hydrogen or methyl;
[000217] R ¹¹ is carboxy, -P (O) (OH) (OR ^c ) or a group of the formula (IB) (as described above);
[000218] X is -NH- or -NHC (O) -;
[000219] R ¹² is hydrogen or methyl;
[000220] R ¹³ is hydrogen, C1-4alkyl or carbocyclyl; wherein R ¹³ is optionally substituted by one or more substituents selected from R ²⁰ ;
[000221] R ¹⁴ is hydrogen;
[000222] R ¹⁵ is carboxy or sulfo;
[000223] R ¹⁷ is selected from halo, hydroxy, C1-4 alkyl or C1-4 alkoxy; wherein R ¹⁷ can be optionally substituted on carbon by means of one or more of R ²¹ ;
[000224] R ²⁰ is hydroxy, carboxy, carbocyclyl or amino; wherein R ²⁰ can be optionally substituted on carbon by means of one or more of R ²² ;
[000225] R ²¹ is selected from the halo;
[000226] R ²² is hydroxy;
[000227] p is 1 to 3; where the values of R ¹³ can be the same or different, [000228] q is 0 to 1;
[000229] r is 0-3; wherein the values of R ¹⁴ can be the same or different; and where q is 1, r is not 0;
[000230] m is 0 to 2; and
Petition 870190089048, of 09/09/2019, p. 40/121
26/70 [000231] n is 1 to 3;
[000232] or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
[000233] Therefore in another, in addition, additional aspect of the invention, at this point a compound of formula (I) is produced as described above in which:
[000234] R ¹ and R ² are independently selected from C 1-4 alkyl;
[000235] R ^x and R ^y are both hydrogen;
[000236] R ^z is selected from halo, amino, C1-6 alkyl, C1-6 alkoxycarbonylamino or ^ '- (C1-6 alkyl) ureido; v is 0 or 1;
[000237] R ³ and R ⁶ are hydrogen;
[000238] one of R ⁴ and R ⁵ is a group of the formula (IA) (as described above) and the other is selected from hydrogen, halo, C1-4 alkoxy or C1-4S alkyl (O) a in which a is 0 to 2; wherein R ⁴ or R ⁵ 'can be optionally substituted on carbon by means of one or more of R ¹⁶ ; wherein R ¹⁶ is independently selected from hydroxy, carboxy and M, M- (C 1-4 alkyl;
[000239] X is -0-;
[000240] R ⁷ is hydrogen, methyl or phenyl;
[000241] R ⁸ is hydrogen or methyl;
[000242] Ring A is aryl or heteroaryl; wherein Ring A is optionally substituted by one or more substituents selected from R ¹⁷ ; wherein R ¹⁷ is selected from halo, hydroxy, C 1-4 alkyl or C 1-4 alkoxy; wherein R ¹⁷ can be optionally substituted on carbon by means of one or more of R ²¹ ; wherein R ²¹ is selected from the halo;
[000243] R ⁹ is hydrogen or methyl;
[000244] R ¹⁰ is hydrogen;
[000245] R ¹¹ is carboxy, -P (O) (OH) (OR ^c ) where R ^c is selected from
Petition 870190089048, of 09/09/2019, p. 41/121
27/70 from C1-4alkyl or a group of the formula (IB) (as described above); [000246] R ¹² is hydrogen or methyl;
[000247] Y is -NH- or -NHC (O) -;
[000248] R ¹³ is hydrogen, C 1-4 alkyl, carbocyclyl or R ²³ ; wherein R ¹³ is optionally substituted by one or more substituents selected from R ²⁰ ; where R ²⁰ is hydroxy, C 1-4 alkyl (O) a where a is 0, C 1-4 alkoxy, amino, carbocyclyl, heterocyclyl or mercapto; wherein R ²⁰ can independently be optionally substituted on carbon by means of one or more of R ²² ; R ²² is selected from hydroxy; and R ²³ is carboxy;
[000249] R ¹⁴ is selected from hydrogen, C1-4 alkyl or carbocyclyl; wherein said C 1-4 alkyl or carbocyclyl can be optionally substituted by one or more substituents selected from R ²⁰ ; and R ²⁰ is hydroxy;
[000250] 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 ) where R ^e and R ^f are independently selected from C 1-4 alkyl or R ¹⁵ is a group of the formula (IC) (as described above);
[000251] R ²⁴ is hydrogen;
[000252] R ²⁵ is hydrogen;
[000253] R ²⁶ is carboxy;
[000254] p is 1 to 3; wherein the values of R ¹³ can be the same or different;
[000255] q is 0 to 1;
[000256] r is 0-3; wherein the values of R ¹⁴ can be the same or different;
[000257] m is 0-2; wherein the values of R ¹⁰ can be the same or different;
[000258] n is 1 to 2; wherein the values of R ⁷ can be the same or different;
Petition 870190089048, of 09/09/2019, p. 42/121
28/70 [000259] z is 0 to 1; wherein the values of R ²⁵ can be the same or different;
[000260] or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof. In another aspect of the invention, the preferred compounds of the invention are any one of the Examples or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
[000261] In another aspect of the invention, the preferred compounds of the invention are any of the Examples or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
[000262] One aspect of the invention is a compound of formula II
R ¹
Formula II where [000263] M is CH ₂ or NH;
[000264] R ¹ is H or hydroxy;
[000265] R ² is H, CH ₃ , -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, CH (CH ₃ ) ₂ , -CH ₂ CH (CH ₃ ) ₂ , -CH (CH ₃ ) CH ₂ CH ₃ , -CH2OH , -CH2OCH3, CH (OH) CH ₃ , -CH2SCH3, or -CH2CH2SCH3;
[000266] for use in the prophylaxis or treatment of liver disease.
[000267] Examples of useful substances according to the invention are:
[000268] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N (carboxymethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3 , 4,5-tetrahydroPetition 870190089048, of 09/09/2019, p. 43/121
29/70
1.2.5- benzothiadiazepine, [000269] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N '- ((S) - 1carboxyethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine, [000270] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio- 8- (N - {(R) -a- [N '- ((S) -1carboxypropyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-
1.5- benzothiadiazepine, [000271] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (V - {(R) -a- [V - ((R) -1 carboxy- 2-methylthioethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, [000272] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7- methylthio-8- (V - {(R) -a- [V - ((S) -1carboxypropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5tetrahydro-1,2,5- benzothiadiazepine, [000273] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (V - {(R) -a- [V - ((R) -1carboxy-2-methylthio -ethyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -
2.3.4.5- tetrahydro-1,2,5-benzothiadiazepine, [000274] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (V - {(R) -a - [V - ((S) -1carboxy-2-methylpropyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, [000275] 1,1-Dioxo-3 , 3-dibutyl-5-phenyl-7-methylthio-8- (V - {(R) -a- [V - ((S) -1carboxy-2- (R) -hydroxypropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -
2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, [000276] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (V - {( R) -a- [V - ((S) -1carboxybutyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, [000277] 1,1 - Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (V - {(R) -a- [V - ((S) -1carboxyethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4 , 5-tetrahydro-1,2,5benzothiadiazepine, [000278] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N '- (((S) -1carboxypropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5 Petition 870190089048, 09/09/2019, p. 44/121
30/70 tetrahydro-1,5-benzothiazepine, [000279] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (M - {(R) -a- [M - (((S) -1carboxyethyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, [000280] 1,1 -Dioxo-3,3-dibutyl -5-phenyl-7-methylthio-8- (M - {(R) -a- [M - ((S) -1carboxy-2-methylpropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -
2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine and [000281] 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.
[000282] The compounds of formula (I) or formula (II) may have chiral centers and / or geometric isomeric centers (E- and Z-isomers), and it is to be understood that the invention encompasses all such optical isomers, diastereoisomers and geometries that have IBAT inhibiting activity. The invention relates to any and all tautomeric forms of the compounds of formula (I) or formula (II) which have IBAT inhibitory activity.
[000283] The invention also relates to all possible isomers of the compounds of the invention, such as optical and / or geometric, pure or a mixture, in all proportions, of said compounds of formulas I and II and specifically those mentioned and the possible tautomeric forms.
[000284] In certain embodiments, the compounds described here have one or more chiral centers. As such, all stereoisomers are considered here. In the various embodiments, the compounds described here are present in optically active or racemic forms. It is to be understood that the compounds of the present invention encompass the racemic, optically active, regioisomeric and stereoisomeric forms, or combinations thereof which have the therapeutically useful properties described herein. The preparation of optical forms
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31/70 active substances is obtained in any suitable way, including by means of the non-limiting example, by solving the racemic form by means of recrystallization techniques, by means of synthesis from optically active starting materials, by means of chiral synthesis, 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, contain one or more chiral centers. These compounds are prepared by what means, including enantioselective synthesis and / or separation of a mixture of enantiomers and / or diastereomers. The resolution of dosisomers and compounds thereof is achieved by any means including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, chromatography, and the like.
[000285] The compounds can exist in an acid-free or acid-free form, or in a pharmaceutically acceptable salt form. In certain embodiments, a compound described herein exists in a solvated or unsolvated form, wherein the solvated forms comprise any pharmaceutically acceptable solvent, for example, water, ethanol, and the like.
[000286] The invention also relates to a composition comprising at least one IBAT inhibitor of Formula (I) or Formula (II), for use in the prophylaxis and / or treatment of a liver disease.
[000287] One aspect of the invention is the use of a compound of Formula (I) or Formula (II), for the preparation of a medicament for the treatment of liver disease.
[000288] An IBAT inhibitor of Formula I or Formula II can be used together with at least one other therapeutically active compound as described here, in the preparation of a medication
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32/70 for the prophylactic and / or therapeutic treatment of liver disease.
Liver disease [000289] Liver disease is defined here as any disease dependent on bile acid (BA) in the liver and the organs connected with it, such as the portal vein of the pancreas, the liver parenchyma, the biliary tree intrahepatic, the extrahepatic bile tree, and the gallbladder.
[000290] The ileal bile acid transporter (IBAT) is the main mechanism for the reabsorption of bile acids from the GI tract. The partial or complete block of that mechanism will result in the lowest concentration of bile acids in the small intestine wall, in the portal vein, in the liver parenchyma, in the intrahepatic biliary tree, in the extrahepatic biliary tree, and in the gallbladder. The diseases that can benefit from partial or complete blockage of the IBAT mechanism may be those with a primary pathophysiological defect, causing or having symptoms of very high concentration of bile acids in the serum and organs above.
[000291] One aspect of the invention is a compound of Formula (I) or Formula (II) as defined above, for use in the prophylaxis or treatment of liver parenchyma; an inherited metabolic disorder of the liver; Byler syndrome; a primary defect in bile acid (BA) synthesis, such as cerebrotendinous, or xanthomatosis; a secondary defect, such as Zellweger syndrome, neonatal hepatitis, cystic fibrosis, liver manifestations, ALGS (Alagilles syndrome), PFIC (progressive familial intrahepatic cholestasis, autoimmune hepatitis, primary biliary cirrhosis (PBC), liver fibrosis, non-alcoholic fatty liver disease, NAFLD / NASH, portal hypertension, general cholestasis such as jaundice due to drugs or during pregnancy, intra and extrahepatic cholestasis, such as hereditary forms of cholestasis, such as
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33/70 mo, PFIC1, Primary sclerosing cholangitis, gallstones and choledocholithiasis, malignancy causing obstruction of the biliary tree, symptoms (itching, itching) due to cholestasis / jaundice, pancreatitis, chronic autoimmune disease of the liver leading to progressive cholestasis, or itching cholestatic liver disease.
[000292] One aspect of the invention is a compound of Formula (I) or Formula (II) as defined above, for use in the prophylaxis or treatment of a liver disorder or a related liver condition, fatty liver, fatty liver, non-alcoholic steatoepatitis ( NASH), alcoholic hepatitis, acute fatty liver, fatty liver of pregnancy, drug-induced hepatitis, iron overload disorders, liver fibrosis, liver cirrhosis, hepatoma, viral hepatitis and problems with tumors and neoplasms of the liver, biliary tract and the pancreas.
Combination with other substances [000293] One aspect of the invention is an IBAT inhibitor according to Formula (I) or Formula (II) as defined above, in combination with at least one other therapeutically active substance. At least one other therapeutically active substance may be an IBAT-inhibiting compound.
Incretins and hormones produced by L cells [000294] At least one other therapeutically active substance can be Incretin or a hormone produced by L cells.
[000295] In one aspect of the invention, at least one other therapeutically active substance is an L cell endocrine peptide enhancer, such as a GLP-1 enhancer. Examples of a GLP-1 enhancer useful according to the invention are GLP-1, a GLP-1 secretion enhancer, an inhibitor of GLP-1 degradation, or a combination thereof.
[000296] In one aspect of the invention, the peptide enhancer from
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34/70 L cell endocrine is a GLP-2 enhancer, such as GLP-2, a GLP-2 secretion enhancer, an inhibitor of GLP2 degradation, or a combination thereof.
[000297] In one aspect of the invention the L cell endocrine peptide enhancer is a PYY enhancer, such as an oxintomodulin enhancer.
Incretin Mimetics [000298] In one aspect of the invention, at least one other therapeutically active substance is an incretin mimetic, such as exenatide (Byetta®).
[000299] One aspect of the invention is an oral combination of an IBAT inhibitor of Formula (I) or Formula (II) as described herein and an inhibitor of DPP-IV.
Enteroendocrine Peptides [000300] In one aspect of the invention, at least one other therapeutically active substance of an enteroendocrine peptide, such as GLP-1 or GLP-1 analogs, for example, Taspoglutide® (Ipsen), or the like.
Combination Therapy with an IBAT inhibitor and a DPP-IV inhibitor [000301] In one aspect of the invention, at least one other therapeutically active substance is a DPP-IV inhibitor.
[000302] One aspect of the invention is a combination of an IBAT inhibitor and metformin and / or sitagliptin (Janumet®) and / or suitable DPP-IV inhibitors for use with the methods described here includes but is not limited to (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- (2,4,5trifluorophenyl) 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
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35/70 (saxagliptin), and 2 - ({6 - [(3R) -3-aminopiperidin-1-yl] -3-methyl-2,4-Dioxo3,4-dihydropyrimidin-1 (2H) -il } methyl) benzonitrile (alogliptin).
TGR5 Receptor Modulators [000303] In one aspect of the invention, at least one other therapeutically active substance is a TGR5 agonist. Modulators of TGR5 (e.g., agonists) include, but are not limited to, the compounds described in WO 2008/091540, WO 2008/067219 and United States Order No. 2008/0221161. Thiazolidinediones [000304] In one embodiment of the invention, at least one other therapeutically active substance is a thiazolidinedione, such as Rosiglitazone (Avandia), Pioglitazone (Actos), Troglitazone (Rezulin), MCC-555, rivoglitazone, ciglitazone or the like.
Combination Therapy with an IBAT INHIBITOR, a Biliary Bypass and a DPP-IV inhibitor [000305] In one embodiment of the invention, a Formula (I) or Formula (II) IBAT INHIBITOR as described herein, is administered in combination with a DPP-IV inhibitor and / or a biliary bypass. Examples of biliary deviations include, but are not limited to, the deviations described in WO 2007/0050628, the description of which is incorporated herein by reference.
[000306] As used here, the term additive effect describes the combined effect of two (or more) pharmaceutically active agents that is equal to the sum of the effect of each agent administered alone. A synergistic effect is one in which the combined effect of two (or more) pharmaceutically active agents is greater than the sum of the effect of each agent administered alone. Any suitable combination of an ASBTI with one or more of the other active ingredients mentioned above and optionally with one or more other pharmacologically active substances is considered to be within the specification 870190089048, of 09/09/2019, pg. 50/121
36/70 cup of the methods described here.
[000307] In some embodiments, the specific choice of compounds depends on the diagnosis of the attending physicians and their judgment of the individual's condition and the appropriate treatment protocol. The compounds are optionally administered simultaneously (for example, simultaneously, essentially simultaneously or within the same treatment protocol) or in sequence, depending on the nature of the disease, disorder, or condition, the condition of the individual, and the current choice of compounds employed. In certain cases, the determination of the order of administration, and the number of repetitions of administration of each therapeutic agent during a treatment protocol, is based on an assessment of the disease to be treated and the condition of the individual.
[000308] In some embodiments, therapeutically effective dosages vary when drugs are used in treatment combinations. Methods for experimentally determining therapeutically effective dosages of drugs and other agents for use in combining treatment regimens are described in the literature.
[000309] In some modalities of the combination therapies described here, the dosages of the co-administered compounds vary depending on the type of co-drug used, the specific drug used, the disease or condition to be treated and so on. In addition, when co-administered with one or more biologically active agents, the compound provided here is optionally administered either simultaneously with the biologically active agent (s), or in sequence. In certain cases, if administered in sequence, the attending physician will decide the appropriate sequence of the therapeutic compound described here in combination with the additional therapeutic agent.
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37/70 [000310] The multiple therapeutic agents (at least one of which is a therapeutic compound described here) are optionally administered in any order or even simultaneously. If simultaneously, multiple therapeutic agents are optionally provided in a single, unified form, or in multiple forms (by way of example only, either as a single pill or as two separate pills). In certain cases, one of the therapeutic agents is optionally given in multiple doses. In other cases, both are optionally given as multiple doses. If not simultaneous, the time between multiple doses is any suitable time, for example, from more than zero weeks to less than four weeks. In addition, formulations, compositions and methods of combination are not to be limited to the use of just two agents; the use of multiple therapeutic combinations is also considered (including two or more compounds described here).
[000311] In certain embodiments, a dosage regimen to treat, prevent, or improve the condition (s) for which relief is sought, is modified according to a variety of factors. These factors include the subject's disorder, as well as the patient's age, weight, sex, diet, and medical condition. Thus, in the various modalities, the dosage regimen currently employed varies and deviates from the dosage regimens established here.
[000312] In some embodiments, the pharmaceutical agents that produce the combination therapy described herein are provided in a combined dosage form or in separate dosage forms intended for substantially simultaneous administration. In certain embodiments, the pharmaceutical agents that produce the combination therapy are administered in sequence, with any therapeutic compound being administered through a regimen.
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38/70 requiring two steps of administration. In some embodiments, the two-stage administration regime requires sequential administration of active agents or administration that is separate from separate active agents. In certain embodiments, the time period between the multiple administration steps varies, by means of the non-limiting example, from a few minutes to several hours, depending on the properties of each pharmaceutical agent, such as the potency, solubility, bioavailability, half-life plasma and kinetic profile of the pharmaceutical agent.
[000313] The invention also relates to the IBAT inhibitor compounds described here in combination with at least one bile acid binder, for example, a resin, such as cholestyramine, colestipol and colesevelam.
Bile acid binders (resins, bile acid scavengers) [000314] In an embodiment of the invention, an IBAT inhibitor of Formula (I) or Formula (II) as defined above, can be administered as a pharmaceutical formulation also comprising at least one bile acid binder, said formulation being designed to release the bile acid binder in the colon and IBAT inhibitor in the small intestine.
[000315] Examples of useful bile acid binders according to the invention are Cholestyramine, which is a hydrophilic polyacrylic quaternary ammonium anion exchange resin, known to be effective in reducing blood cholesterol levels. Cholestyramine, and various compositions including cholestyramine, are described, for example, in British Patent Nos. 929,391 and 1,286,949; and United States Patents 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
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39/70
Light), Upsher-Smith (PREVALITE (D), and Apothecon. As used herein, cholestyramine includes any such composition comprising cholestyramine, or pharmaceutically acceptable salts thereof. These are also called Questrans®.
[000316] Questran Light Questrans Light (cholestyramine) is a non-absorbable anion-binding resin. FDA approved for the treatment of hypercholesterolemia.
[000317] An amine polymer having a first substituent, attached to a first amine of the amine polymer, which includes a hydrophobic aliphatic moiety, and a second substituent, attached to a second amine of the amine polymer, which includes an amine-containing moiety aliphatic quaternary as described in USP 5,693,675 and 5,607,669.
[000318] The salt of a cross-linked and alkylated polymer comprising the reaction product of: (a) one or more cross-linked polymers, or copolymers and salts thereof having a repetition unit selected from the group consisting of: (NR-CH2CH2 ) n (2) and (NRCH2CH2-NR-CH2CH2-NR-CH2CHOH-CH2) n (3) where n is a positive integer and each R, independently, is H or a C 1 -Cs alkyl group; (b) at least one aliphatic alkylating agent, said reaction product characterized by the fact that: (i) at least some of the nitrogen atoms in said repeating units unreacted with said alkylating agent; (ii) less than 10 mol percent of the nitrogen atoms in said repeating units reacting with said alkylating agent forming the quaternary ammonium units; and (iii) a positive fixed charge and one or more against ions, such as, Colesevelam and colesevelam hydrochloride.
[000319] Useful bile acid binders according to the invention are resins, such as cholestyramine and colestipol. An advantage is that the bile acid binder dose could be maintained
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40/70 lower than the therapeutic dose for the treatment of cholesterolemia in the single treatment comprising only a bile acid binder. By a low dose of bile acid binder any possible side effects caused by the patient's low tolerance to the therapeutic dose can also be avoided. [000320] Another useful binder for bile acid is a water-insoluble non-toxic polymeric amine having a molecular weight in excess of 3,000, having the binding property of at least 30% of the available glycocholic acid within 5 minutes when exposed to a aqueous solution of an equal weight of said acid, having a backbone of inert polymer for digestive enzymes, and having a water content greater than 65% after equilibration with air at 100% relative humidity, for example, colestipol described in USP 3,383.28., [000321] In another aspect of the invention a suitable bile acid binder is one of cholestyramine, colestipol or colesevelam.
[000322] A preferred aspect of the present invention is the use of colesevelam as the bile acid binder.
[000323] The compositions of the invention may also comprise statins, for example, an HMG CoA reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in association with a pharmaceutically acceptable carrier or diluent. .
[000324] One embodiment of the invention relates to a combined oral pharmaceutical formulation comprising an IBAT inhibitor compound of Formula (I) or Formula (II) as defined above or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug of the same and a bile acid binder or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug of the same, said formulation being determined to read
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41/70 bile the bile acid binder in the colon and the IBAT inhibitor in the small intestine.
[000325] One embodiment of the present invention is a pharmaceutical formulation comprising a core of a bile acid binder formulated for release into the colon, surrounded by an outer layer comprising an IBAT inhibitor of Formula (I) or Formula (II) as defined above, and formulated for immediate or delayed release in the distal jejunum or the proximal ileum. Statins [000326] In another aspect of the invention, an IBAT-inhibiting compound, for example, a compound of formula (I) or formula (II) as defined above or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug of the same, it can be administered in combination with an HMG CoA reductase inhibitor, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof. Suitable HMG CoA reductase inhibitors, pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof are statins well known in the art. Specific statins are fluvastatin, lovastatin, pravastatin, simvastatin, atorvastatin, cerivastatin, bervastatin, dalvastatin, mevastatin and (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino acid ] pyrimidin-5-yl] (3R, 5S) -3,5-dihydroxyhept-6-enoic (rosuvastatin), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof. A specific statin is atorvastatin, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof. A more specific statin is atorvastatin calcium salt. Another specific statin is (E) -7 [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3R, 5S) -3,5-di -hydroxyhept-6-enoic (rosuvastatin), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a profárma
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42/70 co of it. Another specific statin is the calcium salt of rosuvastatin and pitavastatin (HMG Co A reductase).
[000327] In a further aspect of the invention, the compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug of the same can be administered in association with an HMG CoA reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and / or a bile acid binder thereby preventing a possible risk of excess bile acids in the colon caused by inhibiting the ileal bile acid transporter system. An excess of bile acids in visceral contents can cause diarrhea. Thus, the present invention also provides a treatment for a possible side effect, such as, diarrhea in patients during therapy comprising a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
[000328] An HMG CoA-reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof must by its action decrease the endogenous cholesterol available for the synthesis of bile acid and has an effect additive in combination with a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof in reducing lipids.
[000329] The composition may also comprise a PPAR alpha and / or gamma agonist, or a pharmaceutically acceptable salt thereof.
[000330] A CETP (cholesteryl ester transfer protein) inhibitor, for example, the one referenced and described in WO 00/38725, page 7, line 22, page 10, line 17 that is incorporated
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43/70 here by reference.
A cholesterol absorption antagonist, for example, azetidinones, such as SCH 58235 and that described in US 5,767,115 which is incorporated herein by reference;
The inhibitor of MTP (microsomal transfer protein), for example, that described in Science, 282.751-54, 1998 which is incorporated herein by reference;
A derivative of fibric acid; for example, clofibrate, genfibrozil, fenofibrate, ciprofibrate and bezafibrate;
A derivative of nicotinic acid, for example, nicotinic acid (niacin), acipimox and niceritrol;
A phytosterol compound, for example, represents;
Probucol;
An anti-obesity compound, for example, orlistat (EP 129,748) and sibutramine (GB 2,184,122 and US 4,929,629);
An antihypertensive compound, for example, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin II receptor antagonist, an adrenergic blocker, an alpha adrenergic blocker, a beta adrenergic blocker, a mixed alpha / beta adrenergic blocker, an adrenergic stimulant, calcium channel blocker, a diuretic or a vasodilator;
Insulin;
Sulphonylureas including glibenclamide and / or tolbutamide.
Biguanides
In some embodiments, the additional therapeutic agent is a biguanide. In some cases, biguanides reduce blood glucose levels and / or plasmas. Examples of biguanides include and are not limited to metformin, buformin, phenformin, proguanil or the like.
Acarbose;
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44/70 or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, optionally together with a pharmaceutically acceptable carrier or diluent for a warm-blooded animal, such as a man in need of such therapeutic treatment.
Angiotensin II antagonists [000331] Preferred angiotensin II antagonists, pharmaceutically acceptable salts, solvates, solvates of such salts or a prodrug thereof for use in combination with a compound of formula (I) include, but are not limited to, compounds: candesartan, candesartan cilexetila, losartan, valsartan, irbesartan, tasosartan, telmisartan and eprosartan. Particularly preferred angiotensin II antagonists or pharmaceutically acceptable derivatives thereof for use in the present invention are candesartan and candesartan cilexetil.
[000332] Gamma and / or delta agonists and / or PPAR alpha or an acceptable pharmaceutical salt thereof.
[000333] In another aspect of the invention, the IBAT-inhibiting compound, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug of the same, can be administered in combination with a PPAR alpha and / or gamma agonist, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof. Suitable PPAR alpha and / or gamma agonists, pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof are well known in the art. These include the compounds described in WO 01/12187, WO 01/12612, WO 99/62870, WO 99/62872, WO 99/62871, WO 98/57941, WO 01/40170, J Med Chem, 1996,39,665, Expert Opinion on Therapeutic Patents, 10 (5), 623-634 (in particular the compounds described in the patent applications listed on page 634) and J Med Chem, 2000,43,527 which are all
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45/70 incorporated herein by reference. Particularly an alpha and / or gamma PPAR agonist refers to WY-14643, clofibrate, fenofibrate, bezafibrate, GW 9578, troglitazone, pioglitazone, rosiglitazone, eglitazone, proglitazone, BRL-49634, KRP-297, JTT-501, JTT-501 GW 1929, GW 7845, GW 0207, L-796449, L-165041 and GW 2433.
[000334] Particularly a PPAR alpha and / or gamma agonist refers to (S) -2-ethoxy-3- [4- (2- {4-methanesulfonyloxyphenyl} ethoxy) phenyl] propanoic acid and pharmaceutically acceptable salts thereof.
[000335] According to one embodiment, the substances of the invention are used together with one or more anti-diabetic hypoglycemic active ingredients, cholesterol absorption inhibitors, PPAR delta agonists, fibrates, MTP inhibitors, bile acid absorption inhibitors, polymeric bile acid absorbers, LDL receptor inducers, ACAT inhibitors, antioxidants, lipoprotein lipase inhibitors, ATP-citrate lyase inhibitors, squalene synthase inhibitors, lipoprotein (a) antagonists, HM74A receptor agonists, lipase inhibitors , insulins, sulfonylureas, biguanides, meglitinides, thiazolidinediones, alpha glucosidase inhibitors, the active ingredients that act in the ATP-dependent potassium channel of beta cells, glycogen phosphorylase inhibitors, glucagon receptor antagonists, glucokinase activators, gluconeogenesis inhibitors, fructose-1,6-bisphosphatase inhibitors, transporter modulators 4 glucose inhibitors, glutamine-fructose-6-phosphate amidotransferase inhibitors, dipeptidyl peptidase IV inhibitors, 11-beta-hydroxysteroid dehydrogenase 1 inhibitors, tyrosine phosphatase 1B inhibitors, modulators of sodium dependent glucose 1 or 2, modulators of GPR40, hormone-sensitive lipase inhibitors, acetyl CoA carboxylase inhibitors, phosphoenolpyruvate carboxycin inhibitors, glycogen synthase kinase-3 beta inhibitors, protein kinase C beta inhibitors, re antagonists
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46/70 endothelin A receptor, kappaB kinase I inhibitors, glucocorticoid receptor modulators, CART agonists, NPY agonists, MC4 agonists, orexin antagonists, H3 agonists, TNF agonists, CRF agonists, BP antagonists CRF, urocortin agonists, beta 3 agonists, CB1 receptor antagonists, MSH (melanocyte stimulating hormone) agonists, CCK agonists, serotonin reuptake inhibitors, mixed serotonergic and noradrenergic compounds, 5HT agonists, agonists bombesin, galanin antagonists, growth hormones, growth hormone release compounds, TRH agonists, decoupling protein modulators 2 or 3, leptin agonists, DA agonists (bromocriptine, Doprexin), lipase / amylase inhibitors, PPAR modulators, RXR modulators or amphetamines or TR-beta agonists.
[000336] One aspect of the invention is a method for the treatment of a liver disease, in which an IBAT inhibitor of Formula (I) or Formula (II) as defined above is brought into contact with the distal ileus of an individual with need for such treatment.
[000337] In an embodiment of the invention, an IBAT inhibitor of Formula (I) or Formula (II) as defined above, is administered in combination with a second therapeutic agent selected from a DPP-IV inhibitor, a thiazolidinedione, or an analog thereof, or a TGR5 agonist.
[000338] In certain embodiments, the IBAT inhibitor compounds described here are combined with or used in combination with one or more of the therapeutic agents that follow in any combination: insulin, insulin mimetics, DPP-IV inhibitors, or TGR5 modulators .
[000339] Other active substances to be combined with one or more IBAT inhibitors of the invention can be chosen from
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47/70 one or more of the following substances:
[000340] Ursodeoxycholic acid; non-ursodeoxycholic acid; Rifampicin and related rifamycin derivatives as described in US 3,342,810; opioid antagonists, such as, Naloxone and Naltrexone; serotonin antagonists, such as, 5HT3 receptor antagonists and 5 HT2 antagonists, for example, Trazodone, Nefazodone, Amoxapine, Clozapine; antihistamines, such as, Bronpheniramine, Chlorpheniramine, Dimenhydrinate, Diphenhydramine, Doxylamine Loratadine Cetirizine; serotonin re-uptake inhibitors, such as, Citalopram, Dapoxetine, Escitalopram, Fluoxetine, Fluvoxamine, lindalpin, Pparoxetine, Sertraline, Zimelidine; corticosteroids, such as glucocorticoids and mineralocorticoids, for example, chosen from Hydrocortisone (Cortisol), Cortisone and acetate, Prednisone, Prednisolone, Methylprednisolone, Dexamethasone, Betamethasone, Triamcinolone, Beclomethasone, Fludrocortisone and Acetate and Acetate (ACE) and Acetate and acetate Aldosterone.
[000341] Examples of PPAR delta agonists are GW-501516 (501516, GSK-516, GW-516, GW-1516; a peroxisome proliferator activated receptor (PPAR) -delta agonist, and several other compounds developed at from GW-501516, including GI262570, GW-0072, GW-7845 and GW-7647.
[000342] According to a modality the BAT inhibitor can be combined with one or more of Atreleuton, Eprotirome, Losmapimod, Ezetimibe (SCH58235) Bezafibrato, Fenofibrato, Varespladib, Darapladib, Lomitapide, Implitapide, Rosiglitazona, Loracetrapin, Anacetrapin, Dapagliflozin, Canagliflozin, Sergliflozin ASP-1941 Orlistat, Pioglitazona, Sodelglitazar, Netoglitazona, Indeglitazar, Naveglitazar, Lobeglitazone, Aleglitazar, Bromocriptine, Tesofensine, Monoamine, Allogliptin, Saxofilin, Tryptogliptin, Tryptophaginin, Tryptophan 150444, niacin
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48/70 prolonged release of Laropiprant, Ezetimibe simvastatin, Rosuvastatin fenofibrate, Rosuvastatin Ezetimibe and atorvastatin Ezetimibe.
[000343] Combinations with Tredaptive, Vytorin and Certriad can be used.
[000344] According to one embodiment, the IBAT inhibitor can be combined with one or more of any of the other compounds mentioned above.
[000345] According to one embodiment, the IBAT inhibitors of the present invention are combined with at least one other active substance selected from dipeptidyl peptidase IV inhibitors, PPAR γ agonists, statins and bile acid binders in any combination.
[000346] According to one embodiment, the IBAT inhibitors of the present invention are combined with at least one DPPIV, at least one PPAR γ agonist, such as Sitagliptin and Pioglitazon.
[000347] According to another embodiment, the IBAT inhibitors of the present invention are combined with at least one DPPIV and at least one statin, for example, Sitagliptin and Simvastatin.
[000348] Another active substance that can be combined with the IBAT inhibitors of the invention is ursodeoxycholic acid.
[000349] According to one embodiment the invention relates to a composition comprising one or more IBAT inhibitors of the invention and cholestyramine and / or colesevelam and / or colestipol.
[000350] According to one embodiment the invention relates to a composition comprising one or more of the compounds of Example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14 and cholestyramine and / or colesevelam and / or colestipol.
[000351] According to the modality the invention refers to a
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49/70 composition comprising one or more of the 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-1,5benzothiazepine (Example 5) and cholestyramine and / or colesevelam and / or colestipol.
[000352] According to the embodiment the invention relates to a composition comprising one or more of the 1,1 Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (M - {(R) -a- [M - ((S) -1-carboxy-2methylpropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine (Example 13), and cholestyramine and / or colesevelam and / or colestipol.
[000353] According to the embodiment the invention relates to a composition comprising one or more of the 1,1 Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) compounds -1'-phenyl-1 '- [N' - (carboxymethyl) carbamoyl] methyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5benzothiazepine (Example 14) and cholestyramine and / or colesevelam and / or colestipol.
Vehicles and excipients [000354] The compositions of the invention can also comprise a pharmaceutically acceptable vehicle or diluent.
[000355] Pharmaceutical compositions can be formulated as known in the art employing one or more physiologically acceptable vehicles including, for example, excipients and depending on the route of choice of administration.
[000356] A vehicle includes, in some embodiments, a pharmaceutically acceptable excipient and is selected on the basis of compatibility with the compounds described here, such as the compounds of any of formula I and II, and the properties of the release profile of the desired dosage form.
[000357] Exemplary supporting materials include, for example,
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50/70 binders, suspending agents, disintegrating agents, loading agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents.
[000358] Pharmaceutical compositions and vehicles are described, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa .: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. and Lachman, L, Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).
[000359] A mixture of a compound of Formula I and II and possibly also other active compounds mentioned here, with other chemical components, such as, vehicles, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and / or excipients can be formulated into a composition. In certain embodiments, the therapeutically effective amounts of the compounds described herein are administered in a pharmaceutical composition for an individual having a disease, disorder, or condition to be treated. In specific modalities, the individual is a human. The compounds described herein are either used separately or in combination with one or more additional therapeutic agents.
[000360] In certain embodiments, the pharmaceutical formulations described herein are administered to an individual in any way, including one or more of the multiple routes of administration, such as, by way of non-limiting example, oral, parenteral (for example , intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal.
[000361] The pharmaceutical compositions described here are formulated as a dosage form. As such, in some modalities
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51/70 des, provided here a dosage form comprising a compound described herein, suitable for administration to an individual. In certain embodiments, suitable dosage forms include, by way of non-limiting example, aqueous oral dispersions, liquids, gels, syrups, elixirs, pastes, suspensions, solid oral dosage forms, aerosols, controlled release formulations, fusion formulations rapid, effervescent formulations, lyophilized formulations, tablets, powders, pills, pills, capsules, delayed-release formulations, prolonged-release formulations, pulsatile-release formulations, multi-particulate formulations, and mixed-release and controlled-release formulations.
[000362] In the solid dosage forms described herein optionally include an additional therapeutic compound described here and one or more pharmaceutically acceptable additives, such as, compatible vehicle, binder, loading agent, suspending agent, flavoring agent, sweetening agent, disintegrating, dispersing agent, surfactant, lubricant, dye, diluent, solubilizer, wetting agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, antioxidant, preservative, or one or more combinations thereof. In some aspects, the coating using standard procedures such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000), a film coating is provided around the formulation of the compound of Formula II-G. In one embodiment, a compound described here is in the form of a particle and some or all of the particles of the compound are coated. In certain embodiments, some or all of the particles of a compound described here are microencapsulated. In some embodiments, the compound particles described here are not microencapsulated and are uncoated.
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52/70
Treatment method [000363] The invention also relates to a method for the treatment and / or prophylaxis of a liver disease, in a warm-blooded animal, such as, man, in need of such treatment and / or prophylaxis comprising administering an effective amount of a compound or composition according to the invention for the individual.
[000364] A method for treating any of the diseases or conditions described here in an individual in need of such treatment, may involve the administration of pharmaceutical compositions containing at least one IBAT inhibitor described here, or a pharmaceutically acceptable salt, N - pharmaceutically acceptable oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in amounts therapeutically effective for said individual. Dosage forms [000365] Solid dosage pharmaceutical forms may optionally include additional therapeutic compounds and one or more pharmaceutically acceptable additives, such as a compatible vehicle, binder, filler, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersing agent, surfactant, lubricant, dye, diluent, solubilizer, wetting agent, plasticizer, stabilizer, penetration enhancer, wetting agent, antifoaming agent, antioxidant, preservative, or one or more combinations thereof. In some aspects, the coating using standard procedures such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000), a film coating is provided around the formulation of the compound of Formula II-G. In one embodiment, a compound described here is in the form of a particle and some or
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53/70 all particles of the compound are coated. In certain embodiments, some or all of the particles of a compound described here are micro-encapsulated. In some embodiments, the compound particles described here are not microencapsulated and are not coated.
[000366] An IBAT inhibitor of Formula I and II can be used in the preparation of drugs for the prophylactic and / or therapeutic treatment of obesity and / or diabetes. A method for treating any of the diseases or conditions described here in an individual in need of such treatment, involves administering pharmaceutical compositions containing at least one IBAT inhibitor described here, or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide , pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in amounts therapeutically effective for said individual.
[000367] A dosage form comprises a matrix that allows for the controlled release of an active agent in the distal jejunum, proximal ileum, distal ileum and / or the colon. In some embodiments, a dosage form comprises a polymer that is sensitive to pH (for example, an MMX.TM. matrix from Cosmo Pharmaceuticals) and allows for the controlled release of an active agent into the ileum and / or the colon. Examples of such pH sensitive polymers suitable for controlled release include and are not limited to polyacrylic polymers (for example, anionic polymers of methacrylic acid and / or esters of methacrylic acid, for example, Carbopol.RTM polymers., (CAS number 9063-87-0;) which comprise acidic groups (for example, -COOH, -SO3H) and swell at the basic pH of the intestine (for example, pH of about 7 to about 8). adequate dosage for controlled release in the distal ileum with
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54/70 comprises the microparticulate active agent (for example, micronized active agent). In some embodiments, a non-enzymatically degrading poly (dl-lactideoco-glycolide) (PLGA) nucleus is suitable for the release of an IBAT to the distal ileum. In some embodiments, a dosage form comprising an IBAT is coated with an enteric polymer (eg, Eudragit.RTM. S-100, cas number 25086-15-1), cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethyl cellulose phthalate , anionic polymers of methacrylic acid, esters of methacrylic acid or the like) for release at the specific location for the ileum and / or colon. In some embodiments, the bacterially activated systems are suitable for objective release to the ileum. Examples of activated microflora systems include dosage forms comprising pectin, galactomannan, and / or glycoside conjugates and / or Azo hydrogels (e.g., D-galactoside conjugates, beta-D-xylopyranoside or the like) of the active agent. Examples of micro-flora gastrointestinal enzymes include bacterial glycosidases, such as, for example, D-galactosidase, beta-D-glycosidase, alpha-L-arabinofuranosidase, betaD-xylopyranidasidase or the like.
[000368] The coated units can be loaded into hard gelatin capsules or mixed with tablet excipients, such as fillers, binders, disintegrants, lubricants and other pharmaceutically acceptable additives, and be compressed into the tablets. The pressed tablet is optionally coated with film-forming agents to obtain a smooth tablet surface and also enhance the mechanical stability of the tablet during packaging and transportation. Such a tablet coating, which can be applied to a multi-unit tablet or a conventional tablet, can also comprise additives such as anti-stick agents, dyes and pigments or other additives 870190089048, from 09/09/2019, pg. 69/121
55/70 you to improve the appearance of the tablet.
[000369] The drugs suitable for the new formulations are the IBAT inhibitor compounds, as described in the documents discussed above, hereby incorporated by reference.
[000370] The IBAT-inhibiting compound may alternatively be a low-permeability drug as defined in the Biopharmaceutical Classification System proposed by the FDA.
[000371] A combination therapy according to the invention should preferably comprise the administration simultaneously, separately or in sequence of an IBAT inhibiting compound and a bile acid binder. The IBAT inhibitor can preferably be formulated for the release of the ileum and the bile acid binder can preferably be the formulation for the release of the colon. Dosage [000372] The compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, should normally be administered to a warm-blooded animal in a unit dose within the range of 5 to 5000 mg per square meter of the animal's body area, that is, approximately 0.1 to 100 mg or 0.01 to 50 mg, and this usually provides a therapeutically effective dose. A unit dose form, such as a tablet or capsule, should generally contain, for example, 1 to 250 mg of the active ingredient. Preferably a daily dose in the range of 1 to 50 mg is used. In another aspect, a daily dose in the range of 0.02 to 20 mg is used. In any case, the daily dose must necessarily be varied depending on the treated host, the specific route of administration, and the severity of the disease to be treated.
[000373] In this way, the ideal dosage can be determined by the doctor who is treating any specific patient.
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56/70 [000374] The size of the dose required for therapeutic or prophylactic treatment must necessarily vary depending on the treated host, the route of administration and the severity of the disease to be treated. A unit dose in the range, for example, from 1 to 100, preferably from 1 to 50 is considered. The daily dose can be administered as a single dose or divided into one, two, three or more unit doses.
[000375] A pharmaceutical formulation according to the present invention with an objective release in the gastro intestinal tract provides a reduced systematic exposure, as can be measured by the area under the plasma concentration of the drug versus the time curve (AUC) or 7ahydroxy- 4-cholesten-3-one (C4), while maintaining or even increasing the therapeutic effect, as measured by the reduction in serum cholesterol.
[000376] A combination therapy comprising an IBAT inhibitor and a bile acid binder preferably comprises a low daily dose of the bile acid binder, such as less than 5 g of a resin, and more preferably less than 2 g. A colon-release dosage form of the bile acid binder can be constructed by any of the principles described above for delayed-release formulations.
[000377] A combination therapy comprising an IBAT inhibitor and a bile acid binder can comprise a low daily dose of the bile acid binder, such as less than 5 g of a resin, and more preferably of less than 4, 3, 2 or less than 1 g. Suitable ranges may be 0.1 to 5 g, 0.5 to 4 g, 1 to 3 g, 2 to 4 g, 2 to 3 g per day. A colon release form of bile acid binder can be constructed by any of the principles described above for delayed release formulations.
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57/70 [000378] A tablet can consist of an inner core of 1 to 1000 mg, for example, 200 to 800 mg, 10 to 400 mg, 10 to 200 mg or 20 to 80 mg of acid binder in a colonic release formulation and an external slide with 1 to 100 mg, 5 to 50 mg, for example, 1 to 20 mg of an IBAT inhibitor.
[000379] The daily dose of IBAT inhibitor and / or bile acid binder can be administered as a single dose or divided into one, two, three or more unit doses.
[000380] The dosage three times a day with 400 mg of colesevelam in a colonic release form should give an appropriate binding of bile acids in the colon as the total luminal volume is expected to be about 100 mL, which is in agreement with an accepted pharmacokinetic calculation volume of 250 to 300 mL for the small intestine. The recommended total daily dose of colesevelam to block the absorption of bile acid from the total intestine of humans is 3750 mg / day.
Set [000381] In addition, the invention relates to a set comprising the compound or composition according to the invention and possibly also an instruction for use.
[000382] According to another aspect of the present invention at this point a set is produced comprising an IBAT inhibitor according to the invention or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and an instruction For use.
[000383] In accordance with another aspect of the present invention at this point a set is produced comprising an IBAT inhibitor according to the invention or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and any of the substances mentioned above for use with
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58/70 combination, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
[000384] According to another aspect of the present invention, a set is produced at this point comprising: a) an IBAT inhibitor according to the invention or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in a first unit dosage form; b) any of the aforementioned substances for use in combination or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof; in a second unit dosage form; and c) container means for containing the first and second dosage forms.
[000385] The Examples considered below are intended to illustrate, but to some extent limit the scope of the invention. All references cited here are hereby incorporated by reference in their entirety.
[000386] The term comprising as an employee here should be understood to include, but not be limited to, the items established.
Example 1 [000387] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N (carboxymethyl) carbamoyl] benzyl} carbamoylmethoxy) -2 , 3,4,5-tetrahydro-
1,2,5-benzothiadiazepine, Mw. 696.89.
[000388] This compound is prepared as described in Example 2 of WO 3022286.
Example 2 [000389] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N '- ((S) -1carboxyethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5benzothiazepine, Mw. 709.92.
[000390] This compound is prepared as described in Example 2 of
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WO 03106482.
Example 3 [000391] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (M - {(R) -a- [M - ((S) -1carboxypropyl) carbamoyl] benzyl } carbamoylmethoxy) -2,3,4,5-tetrahydro-
1.2.5- benzothiadiazepine, Mw. 724.94.
[000392] This compound is prepared as described in Example 6 of WO 3022286.
Example 4 [000393] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (M - {(R) -a- [M - ((R) -1carboxy-2-methylthioethyl ) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, Mw. 757.01.
[000394] This compound is prepared as described in Example 7 of WO 3022286.
Example 5 [000395] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (M - {(R) -a- [M - ((S) -1carboxypropyl) carbamoyl] - 4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5tetrahydro-1,2,5-benzothiadiazepine, Mw. 740.94.
[000396] This compound is prepared as described in Example 29 of WO 3022286.
Example 6 [000397] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (M - {(R) -a- [M - ((R) -1carboxy-2-methylthio -ethyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -
2.3.4.5-tetrahydro-1,2,5-benzothiadiazepine, Mw. 773.00.
[000398] This compound is prepared as described in Example 30 of WO 3022286.
Example 7 [000399] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (M - {(R) -a- [M - ((S) -1carboxy-2-methylpropyl ) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, Mw. 738.97.
[000400] This compound is prepared as described in Example 15
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60/70 of WO 3022286.
Example 8 [000401] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (M - {(R) -a- [M - ((S) -1carboxy-2- ( R) -hydroxypropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -
2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, Mw. 756.94.
[000402] This compound is prepared as described in Example 26 of WO 3022286.
Example 9 [000403] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (M - {(R) -a- [M - ((S) -1carboxybutyl) carbamoyl] - 4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, Mw. 754.97.
[000404] This compound is prepared as described in Example 28 of WO 3022286.
Example 10 [000405] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N - ((S) -1carboxyethyl) carbamoyl] benzyl } carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5benzothiadiazepine, Mw. 710.91.
[000406] This compound is prepared as described in Example 5 of WO 3022286.
Example 11 [000407] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N '- ((S) -1carboxypropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5tetrahydro-1,5-benzothiazepine, Mw. 739.95.
[000408] This compound is prepared as described in Example 1 of WO 3022286.
Example 12 [000409] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (M - {(R) -a- [M - ((S) -1carboxyethyl) carbamoyl] - 4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, Mw. 726.91 [000410] This compound is prepared as described in Example 11
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61/70 of WO 3022286.
Example 13 [000411] 1,1 -Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (V - {(R) -a- [V - ((S) -1carboxy-2-methylpropyl ) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -
2.3.4.5-tetrahydro-1,2,5-benzothiadiazepine, Mw. 754.97.
[000412] This compound is prepared as described in Example 27 of WO 3022286.
Example 14 [000413] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -1 '-phenyl-1' [N '- (carboxymethyl) carbamoyl ] methyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-
1.5-benzothiazepine, Mw. 695.90.
[000414] This compound is prepared as described in Example 43 of WO 0250051.
Example 15
Pharmaceutical Effect means Inhibitory Effect (%) [000415] ISBT Hu HEK Uptake SPA 13203 IBAT HUM Ileal Bile Acid Transporter Human HEK Glycocholic acid Uptake Radiometric - SPA Inhibitor IC50 Mean IC50 (nM) was determined for the compounds of examples 1 to 14
Test system
Animals [000416] Species of Mouse; ApoE knockout breed; Sub race C57BL / 6; Women; Total number of animals 70; Body weight range from 20 g to 22 g; Supplier Mollegaard's Breeding (Skensved, Denmark); ID cards of the identification method (bar code).
[000417] Acclimatization of at least one week at the Section of Laboratory; Animal Resource from AstraZeneca; Storage conditions maintained every five years in the cages (Makrolon III, 7 dm2) in an environment with regulated temperature (22 ° C), relative humidity (40% to 60%) and a 12/12 light / dark cycle . Access to diet li
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62/70 vre for R3 pellets (Lactamin, Vadstena, Sweden) during storage and trial period. Free access to tap water water during storage and trial period.
[000418] Bedding Sprinkle bed material from aspen wood (Tapvei, Finland).
Experimental procedures [000419] The animals were orally administered with the vehicle (n = 3) or the compound of Example 14 (0.156 (n = 3), 0.625 (n = 3) or 2.5 pmol / kg (n = 3) ) at 1:00 pm on the day of the experiment. Thirty minutes later, a trace amount of ⁷⁵ SeHCAT ( ⁷⁵ Se-homotauro-cholic acid) (0.1 mCi per 0.1 mL per mouse) was given orally to each mouse. Twenty-four hours after the administration of ⁷⁵ SeHCAT, the animals were killed by CO2 inhalation. At sacrifice, the gallbladder and the entire intestine were removed, and feces during the 24-hour period after the administration of ⁷⁵ SeHCAT were collected from each mouse. The ⁷⁵ SeHCAT gamma radioactivities in feces and intestinal gallbladder were separately counted by the 1282 CompuGamma CS Gamma counter (Wallacy, Turku, Finland). The stability as well as the amount of ⁷⁵ SeHCAT administered to each mouse, was controlled with an additional aliquot of ⁷⁵ SeHCAT following the same experimental process as other samples tested in the study.
Data Analysis [000420] The sum of the gamma counters of both the stool and the gallbladder of the intestine was considered to be the total ⁷⁵ SeHCAT recovered, which was calculated to be around 85% of the total ⁷⁵ SeHCAT administered to each mouse. From the radioactivity recovered from ⁷⁵ SeHCAT, the percentage of ⁷⁵ SeHCAT detected in the faeces was considered as fecal excretion at the same time as in the intestinal gallbladder with body retention. The inhibitory effect of the compound of Example 14 on ab
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63/70 intestinal sorption of ⁷⁵ SeHCAT was calculated after body retention of ⁷⁵ SeHCAT and fecal excretion, and the ED50 of the compound was estimated following the dose-effect curve.
Results [000421] The average inhibitory effect of IBAT (%) at a dose of (pmol / kg): 0.156 was determined for the compounds of examples 1 to 14 and is reported in Table 1.
Table 1
Example Structure % of 0.156 pmol / kg inhibition Average ofIC50 nM 1. o, P _h II / ΟΥ- 43 0.45 2. ^^ Y ^ V Vά 55 0.39 3. ΛΑ ΑΑΤ s - | Ά ό 63 0.18 4. 9 .9 · ^ηοΛ Τ ^ν Υ ^ η V% Η ', ΧΑ ΑΑΤ ν5 63 0.35
Petition 870190089048, of 09/09/2019, p. 78/121
64/70
Example Structure % of 0.156 pmol / kg inhibition Average ofIC50 nM 5. OH (j ⁰ LI I ⁰ 'o o.7 ... s- _N r- JJ 74 0.16 6. OH “Vl ^ o ° s °»O 59 - 7.66 0.36 8. OH/ 'OH [^ J] 46 0.11 9. OH 67 -
Petition 870190089048, of 09/09/2019, p. 79/121
65/70
Example Structure % of 0.156 pmol / kg inhibition Average ofIC50 nM 10. O./"Cj 68 0.2 11. HOÒ TheThe h L _., '-.H ° Ο 'O 63 0.15 12. OH° ’0 63 0.3 13. CHCJO 1 O QP ° p ^ y 'ò 68 0.13 14. OThe 1stΗΟ '^ Πγ'Ν' ^ O.í IJ KX /S’N 28 1.2
Example 16
In Vivo Animal Model of Primary Sclerosing Cholangitis (PSC)
Petition 870190089048, of 09/09/2019, p. 80/121
66/70 [000422] A genetic mouse with a targeted breakdown of the gene resistant to multiple drugs Mdr2 (Abcb4) encoding the canalicular phospholipid flippase (Mdr2 - / - mice) spontaneously develops sclerosing cholangitis with macroscopic and microscopic characteristics of human primary sclerosing cholangitis. The bile duct injury in these mice is linked to the secretion of the deficient bile phospholipid resulting in an increased concentration of free non-mycelial bile acids that subsequently causes damage to the bile duct epithelial cell (cholangiocyte), pericolangitis, periductal fibrosis with proliferation ductular and finally sclerosing cholangitis. The gene expression profile has striking similarities revealed between human PSC and Mdr2 - / -. In the analogy for the Mdr2- / - mouse model of sclerosing cholangitis, defects in the MDR3 / ABCB4 multi-drug resistant protein (the human orthologue of the Mdr2 / Abcb4 rodent) play a role in the pathogenesis of various cholangiopathies in humans. MDR3 variants play a role as a modifying gene in the pathogenesis of various cholangiopathies, such as PSC, primary biliary cirrhosis (PBC) and idiopathic adult / biliary fibrosis ductopenia.
[000423] Mdr2 - / - mice were given daily oral doses of the compound of Example 14 by gavage for 2 to 4 weeks and controls were dosed on the vehicle in the same way. Serum liver tests, liver histology and fibrosis were investigated. The compound of Example 14 improves liver tests, liver histology and fibrosis.
Example 17 [000424] A formulation for the delayed release of the IBAT inhibitor having the following composition is to be prepared:
Petition 870190089048, of 09/09/2019, p. 81/121
67/70
Substance quantity / capsule (mg)
IBAT compound inhibitor
Example 14
Non pareil spheres
Ethyl cellulose
500
Hydroxypropylmethyl cellulose
Eudragit L100-55, CAS No: 25212 - 88 Triethylcitrate
2.4 [000425] The IBAT inhibitor compound of Example 14 is dissolved together with ethyl cellulose and hydroxypropyl cellulose in 99% ethanol. The mixture is then sprayed on the non-pareil spheres in a fluid bed apparatus. Accordingly, the pellets are dried and aerated to remove residual ethanol. The Eudragit L100-55 dispersion with the addition of triethyl citrate is then sprayed onto the drug granules in a fluid bed apparatus. Subsequently, the coated granules are loaded into hard gelatin capsules after drying and sieving.
Example 18 [000426] A formulation for delayed release of the IBAT inhibitor having the following composition is prepared:
Ingredient quantity / tablet (mg)
Compound of IBAT inhibitor
Example 1410
Silicon dioxide200
Povidone K-2520
Eudragit FS30D, CAS #: 26936 - 24 - 330
Microcrystalline cellulose250
Sodium stearyl fumarate5 [000427] The IBAT inhibitor compound of Example 14 is suspended in water and sprayed on silicon dioxide cores of a size
Petition 870190089048, of 09/09/2019, p. 82/121
68/70 predefined in a fluid bed apparatus. The drug pellets are dried in an oven at 40 ° C for 24 hours. Accordingly, a layer of Povidone K-25 is applied to the granules from an ethanolic solution in a fluid bed apparatus. A final dispersion coating of Eudragit FS30D is applied accordingly in a fluidized bed. The coated granules are mixed with microcrystalline cellulose and sodium stearyl fumarate in a mixer and subsequently pressed into the tablets. Example 19 [000428] A combination of IBAT inhibitor - colesevelam compressed with immediate release of IBAT inhibitor and colon release of bile acid binder having the following composition is prepared:
Ingredient quantity / tablet (mg)
Core
Colesevelam400 hydrochloride
Microcrystalline cellulose150
Hydroxypropyl methyl cellulose50
Colloidal silicon dioxide10
Magnesium stearate5
Colon release layer
Eudragit FS30D60
PlasACRYL T20, CAS no 123-94-46
IBAT inhibitory layer
Example 147 IBAT inhibitor
Hydroxypropyl methyl cellulose12
Croscarmellose sodium6
Protective coating
Hydroxypropyl methyl cellulose12
Polyethylene glycol2
Petition 870190089048, of 09/09/2019, p. 83/121
69/70 [000429] 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 pressed into the tablets. The dispersion of EUDRAGIT FS30D and water is agitated in PlasACRYL T20 and sprayed on the core tablets using a suitable coating machine. The IBAT inhibitor coating suspension is prepared by mixing the IBAT inhibitor, hydroxypropyl methyl cellulose and croscarmellose sodium in water and sprayed on the tablet cores with the colon release layer using a suitable coating machine. Finally, the protective coating solution of hydroxypropylmethyl cellulose and polyethylene glycol is sprayed onto the tablets using a suitable coating machine.
Example 20 [000430] A colesevelam colon release tablet having the following composition is prepared:
Ingredient quantity / tablet (mg)
Core
Colesevelam400 hydrochloride
Microcrystalline cellulose150
Hydroxypropyl methyl cellulose50
Colloidal silicon dioxide10
Magnesium stearate5
Colon release layer
Amylose30
Eudragit S10060
Triethylcitrate6
Glycerolmonostearate3 [000431] Colesevelam hydrochloride, microcrystalline cellulose and di
Petition 870190089048, of 09/09/2019, p. 84/121
70/70 colloidal silicon oxides are mixed and granulated with hydroxypropyl methyl cellulose dissolved in water. The granules are dried and mixed with magnesium stearate and pressed into the tablets. Amylose, Eudragit 100, triethylcitrate and glycerol monoesterate are dissolved in the appropriate solvents and sprayed onto the tablet cores using a suitable coating machine.

权利要求:
Claims (22)
[1]
1. Compound, characterized by the fact that it presents the
Formula (II),
R ¹

[2]
2. Compound, according to claim 1, characterized by the fact that it is selected from the group consisting of:
1,1 -Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [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) -a- [N '- ((S) -1
Petition 870190089048, of 09/09/2019, p. 86/121
2/7 carboxyethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5benzothiazepine;
1,1 -Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (M - {(R) -a- [M - ((S) -1carboxypropyl) carbamoyl] benzyl} carbamoylmethoxy) -2 , 3,4,5-tetrahydro-
1.2.5- benzothiadiazepine;
1,1 -Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (M - {(R) -a- [M - ((R) -1carboxy-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- (M - {(R) -a- [M - ((S) -1carboxypropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy ) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (M - {(R) -a- [M - ((R) -1carboxy-2-methylthio-ethyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -
2.3.4.5- tetrahydro-1,2,5-benzothiadiazepine; 1,1-Dioxo-3,3-dibutyl-5-phenyl7-methylthio-8- (N - {(R) -a- [N- ( (S) -1-carboxy-2methylpropyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5 benzothiadiazepine;
1,1 -Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (M - {(R) -a- [M - ((S) -1carboxy-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- (M - {(R) -a- [M - ((S) -1carboxybutyl) carbamoyl] - 4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
1,1 -Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (M - {(R) -a- [M - ((S) -1carboxyethyl) 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) -a- [N '- ((S) -1carboxypropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5tetrahydro-1,5-benzothiazepine;
1,1 -Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (W - {(R) -a- [W - ((S) -1
Petition 870190089048, of 09/09/2019, p. 87/121
[3]
3/7 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- (M - {(R) -a- [M - ((S) -1carboxy-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) carbamoyl] methyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-
1.5-benzothiazepine;
or a pharmaceutically acceptable salt thereof.
Compound according to claim 1 or 2, characterized in that it is 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N {(R) -a- [N - (((S) -1-carboxypropyl) carbamoyl] -4hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiazepine, or a pharmacologically acceptable salt thereof.
[4]
Compound according to claim 1 or 2, characterized in that it is 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, or a pharmaceutically acceptable salt thereof.
[5]
Compound according to any one of claims 1 to 4, characterized by the fact that the liver disease is Alagille syndrome (ALGS).
[6]
A compound according to any one of claims 1 to 4, characterized by the fact that the liver disease is progressive familial intrahepatic cholestasis (PFIC).
[7]
Compound according to any one of claims 1 to 4, characterized by the fact that the liver disease is primary biliary cirrhosis (PBC).
[8]
A compound according to any one of claims 1 to 4, characterized by the fact that liver disease is coles
Petition 870190089048, of 09/09/2019, p. 88/121
4/7 general tase.
[9]
Compound according to any one of claims 1 to 4, characterized by the fact that liver disease is cholestasis of pregnancy.
[10]
A compound according to any one of claims 1 to 4, characterized by the fact that the liver disease is primary sclerosing cholangitis (PSC).
[11]
A compound according to any one of claims 1 to 4, characterized by the fact that liver disease is itchy from cholestatic liver disease.
[12]
12. A compound according to any one of claims 1 to 4, characterized by the fact that the liver disease is non-alcoholic steatohepatitis (NASH).
[13]
13. Pharmaceutical composition, characterized by the fact that it comprises a compound of Formula (II), as defined in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, for use as an active ingredient in a prophylaxis and / or treatment of a liver disease selected from the group consisting of Alagilles syndrome (ALGS), progressive familial intrahepatic cholestasis (PFIC), primary biliary cirrhosis (PBC), general cholestasis, cholestasis of pregnancy, primary sclerosing cholangitis (PSC), pruritus of cholestatic liver disease and non-alcoholic steatohepatitis (NASH).
[14]
14. Composition according to claim 13, characterized in that the compound of Formula (II) is 1,1-dioxo-3,3dibutyl-5-phenyl-7-methylthio-8- (N - {(R ) -a- [N - (((S) -1-carboxypropyl) carbamoyl] 4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5benzothiazepine, or a pharmacologically acceptable salt thereof.
[15]
15. Composition according to claim 13, characterized by the fact that the compound of Formula (II) is 1,1-dioxo-3,3
Petition 870190089048, of 09/09/2019, p. 89/121
5/7 dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -1'-phenyl-1 '- [N' (carboxymethyl) carbamoyl] methyl} carbamoylmethoxy) -2,3,4, 5-tetrahydro-1,5benzothiazepine, or a pharmaceutically acceptable salt thereof.
[16]
16. Use of a compound of Formula (II), as defined in any one of claims 1 to 4, or of a pharmaceutically acceptable salt thereof, characterized by the fact that it is in the production of a medicine for the prophylaxis and / or treatment of a liver disease selected from the group consisting of Alagilles syndrome (ALGS), progressive familial intrahepatic cholestasis (PFIC), primary biliary cirrhosis (PBC), general cholestasis, pregnancy cholestasis, primary sclerosing cholangitis (PSC), pruritus of disease cholestatic liver disease and non-alcoholic steatohepatitis (NASH).
[17]
17. Pharmaceutical combination for simultaneous or sequential administration, characterized in that it contains a compound of Formula (II), as defined in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, and ursodeoxycholic acid, for use as active ingredient in a combination of drugs for the prophylaxis and / or treatment of a liver disease selected from the group consisting of Alagilles syndrome (ALGS), progressive familial intrahepatic cholestasis (PFIC), primary biliary cirrhosis (PBC), general cholestasis, cholestasis of pregnancy, primary sclerosing cholangitis (PSC), pruritus of cholestatic liver disease and non-alcoholic steatohepatitis (NASH).
[18]
Pharmaceutical combination for simultaneous or sequential administration, characterized by the fact that it contains a compound of Formula (II), as defined in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, and norursodeoxycholic acid, for use as an ingredient active in a combination of drugs for the prophylaxis and / or treatment of a liver disease selected from the group consisting of Alagilles syndrome
Petition 870190089048, of 09/09/2019, p. 90/121
6/7 (ALGS), progressive familial intrahepatic cholestasis (PFIC), primary biliary cirrhosis (PBC), general cholestasis, pregnancy cholestasis, primary sclerosing cholangitis (PSC), itchy cholestatic liver disease and non-alcoholic steatohepatitis (NASH) .
[19]
19. Combination according to claim 17 or 18, characterized by the fact that the compound of Formula (II) is 1,1-dioxo-
3.3- dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N - ((S) -1carboxypropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4, 5tetrahydro-1,2,5-benzothiazepine, or a pharmacologically acceptable salt thereof.
[20]
20. Combination according to claim 17 or 18, characterized in that the compound of Formula (II) is 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-1,5benzothiazepine, or a pharmaceutically acceptable salt thereof.
[21]
21. Use of a compound of Formula (II), as defined in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, and of ursodeoxycholic acid, characterized in that it is in the preparation of a combination for simultaneous administration or sequential in the prophylaxis and / or treatment of a liver disease selected from the group consisting of Alagilles syndrome (ALGS), progressive familial intrahepatic cholestasis (PFIC), primary biliary cirrhosis (PBC), general cholestasis, cholestasis of pregnancy, cholangitis primary sclerosing (PSC), pruritus of cholestatic liver disease and non-alcoholic steatohepatitis (NASH).
[22]
22. Use of a compound of Formula (II), as defined in any
Petition 870190089048, of 09/09/2019, p. 91/121
7/7 one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, and nor-ursodeoxycholic acid, characterized in that it is in the preparation of a combination for simultaneous or sequential administration in the prophylaxis and / or treatment of a liver disease selected from the group consisting of Alagilles syndrome (ALGS), progressive familial intrahepatic cholestasis (PFIC), primary biliary cirrhosis (PBC), general cholestasis, pregnancy cholestasis, primary sclerosing cholangitis (PSC), itching liver disease cholestatic and non-alcoholic steatohepatitis (NASH).

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

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

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2019-05-21| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

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2019-07-16| B06T| Formal requirements before examination [chapter 6.20 patent gazette]|

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2019-12-17| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2020-02-04| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 08/11/2011, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US41095710P| true| 2010-11-08|2010-11-08|

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SE1051165|2010-11-08|

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PCT/SE2011/051335|WO2012064266A1|2010-11-08|2011-11-08|Ibat inhibitors for the treatment of liver diseases|

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