Benzothiazepine derivatives for the treatment of hyperlipidemia

专利摘要:
The present invention relates to compounds of formula (I) wherein the modifier groups are as defined in the specification) or pharmaceutically acceptable salts, solvates thereof, solvates or prodrugs of such salts and bile acid carriers for the treatment of their hyperlipidemia (IBAT It relates to the use as). Methods of their preparation and pharmaceutical compositions containing them are also described. Formula I
公开号:KR20040031057A
申请号:KR10-2004-7003331
申请日:2002-09-05
公开日:2004-04-09
发明作者:스타르케잉게마르；달스트롬미카엘울프요한；블롬버그데이비드
申请人:아스트라제네카 아베；
IPC主号:

专利说明:

Benzothiazepine derivative for the treatment of hyperlipidemia {BENZOTHIAZEPINE DERIVATIVES FOR THE TREATMENT OF HYPERLIPIDEMIA}
[2] Hyperlipidemia associated with increased concentrations of total cholesterol and low-density lipoprotein cholesterol is well known to be a major risk factor for cardiovascular atherosclerosis disease (eg, "Coronary Heart Disease: Reducing the Risk; a Worldwide View" Assman G., Carmena R. Cullen P. et al .; Circulation 1999, 100, 1930-1938 and "Diabetes and Cardiovascular Disease: A Statement for Healthcare Professionals from the American Heart Association" Grundy S, Benjamin I., Burke G., et al. Circulation, 1999, 100, 1134-46). It is known that obstructing the circulation of bile acids in the lumen of the intestinal tract reduces cholesterol concentrations. Previously established therapies for reducing cholesterol concentrations include, for example, treatment with HMG-CoA reductase inhibitors, preferably statins such as simvastatin and fluvastatin, or treatment with bile acid binders such as resins. Frequently used bile acid binders are, for example, cholestyramine and cholestipol. One recently proposed therapy ("Bile acids and Lipoprotein Metabolism: a Renaissance for Bile Acids in the Post Statin Era" Angelin B, Eriksson M, Rudling M; Current Opinion on Lipidology, 1999, 10, 269-74) Treatment of substances with inhibitory effects.
[3] Resorption of bile acids from the gastrointestinal tract is a normal physiological process that occurs mainly in the ileum by the IBAT mechanism. Inhibitors of IBAT can be used to treat hypercholesterolemia (see, eg, Interaction of bile acids and cholesterol with nonsystemic agents having hypocholesterolaemic properties ", Biochemica et Biophysica Acta, 1210 (1994) 255-287). Suitable compounds with IBAT inhibitory activity are also useful in the treatment of hyperlipidemic conditions Substituted substituted compounds with these IBAT inhibitory activity have already been described, for example WO 93/16055, WO 94/18183, WO 94 /. Hypoglycemic benzothiazepines described in 18184, WO 96/05188, WO 96/08484, WO 96/16051, WO 97/33882, WO 98/38182, WO 99/35135, WO 98/40375 and EP 0 864 582 See compounds.
[4] Other aspects of the invention include hyperlipidemia, hypertriglyceridemia, hyperbetalipoproteinemia (high LDL), classic betaproteinemia (high VLDL), indigenous microlipemia, hypoproteinemia, hypercholesterolemia, hyperlipoproteinemia and hypoalphalipoproteinemia It relates to the use of a compound of the invention in the treatment of aberrant hemostatic conditions and diseases such as (low HDL). In addition, these compounds include atherosclerosis, atherosclerosis, arrhythmia, hyperthrombotic state, vascular insufficiency, endothelial insufficiency, heart failure, coronary heart disease, cardiovascular disease, myocardial infarction, angina pectoris, peripheral vascular disorders, cardiovascular tissues such as heart Inflammation of the plaques, blood vessels, arteries and veins, aneurysms, stenosis, restenosis, blood spots, vascular fat progenitors, leukocytes, monocytes and / or macrophage infiltration, endometrial thickening, medial thinning, infection and trauma and thrombosis, stroke and It is expected to be useful for the prevention and treatment of different clinical conditions such as transient ischemic attacks.
[1] The present invention relates to benzothiazepine derivatives or their pharmaceutically acceptable salts, solvates, solvates and prodrugs of such salts. These benzothiazepines have ileal bile acid transport (IBAT) inhibitory activity and are therefore valuable for the treatment of disease states associated with hyperlipidemia, which are useful as methods of treatment of warm-blooded animals such as humans. The present invention also relates to a process for the preparation of the benzothiazepine derivatives, pharmaceutical compositions containing them and the use thereof in the manufacture of a medicament for inhibiting IBAT in warm blooded animals such as humans.
[5] The present invention is surprisingly based on the discovery that certain benzothiazepine compounds inhibit IBAT. These properties are expected to be of value in the treatment of disease states associated with hyperlipidemia.
[6] Accordingly, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof:
[7]
[8] [In the above formula, one of R ¹ and R ² is selected from hydrogen, C _1-6 alkyl or C _2-6 alkenyl, the other is selected from C _1-6 alkyl or C _2-6 alkenyl;
[9] R ^y is selected from hydrogen, hydroxy, C _1-6 alkyl, C _1-4 alkoxy and C _1-6 alkanoyloxy;
[10] R ^z is halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1- 6} alkoxy, C _1-6 alkanoyl, C _1-6 alkanoyloxy, N- (C _1-6 alkyl) amino, N, N- (C _1-6 alkyl) ₂ amino, C _1-6 alkanoylamino , N- (C _1-6 alkyl) carbamoyl, N, N- (C _1-6 alkyl) ₂ carbamoyl, C _1-6 alkylS (O) _a (where a is 0 to 2), C _1-6 alkoxycarbonyl, N- (C _1-6 alkyl) sulfamoyl and N, N- (C _1-6 alkyl) ₂ sulfamoyl;
[11] v is 0-5;
[12] One of R ⁴ and R ⁵ is a group of formula ( IA )
[13] The other of R ³ and R ⁶ and R ⁴ and R ⁵ is independently hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _1-4 alkanoyl, C _1-4 alkanoyloxy, N- (C _1-4 alkyl) amino, N, N- ( C _1-4 alkyl) ₂ amino, C _1-4 alkanoylamino, N- (C _1-4 alkyl) carbamoyl, N, N- (C _1-4 alkyl) ₂ carbamoyl, C _1-4 Alkyl S (O) _a (where a is 0-2), C _1-4 alkoxycarbonyl, N- (C _1-4 alkyl) sulfamoyl and N, N- (C _1-4 alkyl) ₂ sulfamoyl Wherein the other of R ³ and R ⁶ and R ⁴ and R ⁵ may be optionally substituted on carbon with one or more R ¹⁶ ;
[14] Formula IA
[15]
[16] Wherein X is -O-, -N (R ^a )-, -S (O) _b -or -CH (R ^a ), where R ^a is hydrogen or C _1-6 alkyl and b is 0-2 );
[17] Ring A is aryl or heteroaryl, which is optionally substituted with one or more substituents selected from R ¹⁷ ;
[18] R ⁷ is hydrogen, C _1-4 alkyl, carbocyclic or heterocyclic, which is optionally substituted by one or more substituents selected from R ¹⁸ ;
[19] R ⁸ is hydrogen or C _1-4 alkyl;
[20] R ⁹ is hydrogen or C _1-4 alkyl;
[21] R ¹⁰ is hydrogen, C _1-4 alkyl, carbocyclic or heterocyclic, which is optionally substituted by one or more substituents selected from R ¹⁹ ;
[22] R ¹¹ is carboxy, sulfo, sulfino, phosphono, -P (O) (OR ^c ) (OR ^d ), -P (O) (OH) (OR ^c ), -P (O) (OH) (R ^d ) or —P (O) (OR ^c ) (R ^d ) wherein R ^c and R ^d are independently selected from C _1-6 alkyl, or R ¹¹ is a group of formula IB
[23] Formula IB
[24]
[25] Where Y is -N (R ^x )-, -N (R ^x ) C (O)-, -O-, and -S (O) a-, where a is 0-2 and R ^x is hydrogen or C _1-4 alkyl);
[26] R ¹² is hydrogen or C _1-4 alkyl;
[27] R ¹³ and R ¹⁴ are independently selected from hydrogen, C _1-6 alkyl, carbocyclic or heterocycle, and R ¹³ and R ¹⁴ may be independently substituted by one or more substituents selected from R ²⁰ ;
[28] R ¹⁵ is carboxy, sulfo, sulfino, phosphono, -P (O) (OR ^e ) (OR ^f ), -P (O) (OH) (OR ^e ),-P (O) (OH) (R ^e) or ^{-P (O) (oR e)} (R f) ( wherein, R ^e and R ^f are independently selected from C _1-6 alkyl) or R ¹⁵ is a group of the formula IC to inde,
[29] Chemical Formula IC
[30]
[31] Wherein R ²⁴ is selected from hydrogen or C _1-4 alkyl;
[32] R ²⁵ is selected from hydrogen, C _1-4 alkyl, carbocyclic, heterocyclic or R ²⁷ , wherein C _1-4 alkyl, carbocyclic or heterocyclic is independently substituted by one or more substituents selected from R ²⁸ . Could be;
[33] R ²⁶ is carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P (O) (OR ^g ) (OR ^h ), -P (O) (OH) (OR ^g ), -P (O) (OH ) (R ^g ) or -P (O) (OR ^g ) (R ^h ), wherein R ^g and R ^h are independently selected from C _1-6 alkyl:
[34] p is 1-3 (wherein the groups of R ¹³ may be the same or different);
[35] q is 0 to 1;
[36] r is 0-3, where the groups of R ¹⁴ may be the same or different;
[37] m is 0-2 where the groups of R ¹⁰ may be the same or different;
[38] n is 1-3 (wherein groups of R ⁷ may be the same or different);
[39] z is 0-3, where the groups of R ²⁵ may be the same or different;
[40] R ¹⁶ , R ¹⁷ and R ¹⁸ are independently halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-4 alkyl, C _2-4 alkenyl, C _{2 -4} alkynyl, C _1-4 alkoxy, C _1-4 alkanoyl, C _1-4 alkanoyloxy, N- (C _1-4 alkyl) amino, N, N- (C _1-4 alkyl) ₂ amino , C _1-4 alkanoylamino, N- (C _1-4 alkyl) carbamoyl, N, N- (C _1-4 alkyl) ₂ carbamoyl, C _1-4 alkylS (O) _a (where a is 0-2), C _1-4 alkoxycarbonyl, N- (C _1-4 alkyl) sulfamoyl and N, N- (C _1-4 alkyl) ₂ sulfamoyl, wherein R ¹⁶ , R ¹⁷ and R ¹⁸ may independently be optionally substituted on carbon by one or more R ²¹ ;
[41] R ¹⁹ ,R ²⁰ ,R ²⁷ AndR ²⁸ Are independently halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C_1-4Alkyl, C_2-4Alkenyl, C_2-4Alkynyl, C_1-4Alkoxy, C_1-4Alkanoyl, C_1-4Alkanoyloxy, N- (C_1-4Alkyl) amino, N, N- (C_1-4Alkyl)₂Amino, C_1-4Alkanoylamino, N- (C_1-4Alkyl) carbamoyl, N, N- (C_1-4Alkyl)₂Carbamoyl, C_1-4Alkyl S (O)_a(Where a is 0 to 2), C_1-4Alkoxycarbonyl, N- (C_1-4Alkyl) sulfamoyl, N, N- (C_1-4Alkyl)₂Sulfamoyl, carbocyclic, heterocyclic, sulfo, sulfino, amidino, (C_1-4Alkyl)₃Silyl, 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^aAnd R^bIs independently C_1-6Selected from alkyl) and R¹⁹And R²⁰Is independently 1 or more R²²May be optionally substituted on carbon by;
[42] R ²¹ and R ²² are independently halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl , Ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N , N-dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl and N, N-dimethylsulfamoyl.]
[43] Another feature of the invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, solvate of such salt or prodrug thereof:
[44] Formula I
[45]
[46] [In the above formula, one of R ¹ and R ² is hydrogen or C _1-6 alkyl, the other is selected from C _1-6 alkyl;
[47] R ^y is selected from hydrogen, hydroxy, C _1-6 alkyl, C _1-4 alkoxy and C _1-6 alkanoyloxy;
[48] R ^z is halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1- 6} alkoxy, C _1-6 alkanoyl, C _1-6 alkanoyloxy, N- (C _1-6 alkyl) amino, N, N- (C _1-6 alkyl) ₂ amino, C _1-6 alkanoylamino , N- (C _1-6 alkyl) carbamoyl, N, N- (C _1-6 alkyl) ₂ carbamoyl, C _1-6 alkylS (O) _a , where a is 0 to 2, C _1-6 alkoxycarbonyl, N- (C _1-6 alkyl) sulfamoyl and N, N- (C _1-6 alkyl) ₂ sulfamoyl);
[49] v is 0-5;
[50] One of R ⁴ and R ⁵ is a group of formula ( IA )
[51] Formula IA
[52]
[53] Wherein R ³ and R ⁶ and the other of R ⁴ and R ⁵ are independently hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-4 alkyl , C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _1-4 alkanoyl, C _1-4 alkanoyloxy, N- (C _1-4 alkyl) amino, N, N -(C _1-4 alkyl) ₂ amino, C _1-4 alkanoylamino, N- (C _1-4 alkyl) carbamoyl, N, N- (C _1-4 alkyl) ₂ carbamoyl, C _{1 -4} alkylS (O) _a , where a is 0-2, C _1-4 alkoxycarbonyl, N- (C _1-4 alkyl) sulfamoyl and N, N- (C _1-4 alkyl) ₂ sulfa And the other of R ³ and R ⁶ and R ⁴ and R ⁵ may be optionally substituted on carbon by one or more R ¹⁶ ;
[54] X is -O-, -N (R ^a )-, -S (O) _b -or -CH (R ^a ), where R ^a is hydrogen or C _1-6 alkyl and b is 0-2 ;
[55] Ring A is aryl or heteroaryl, which is optionally substituted with one or more substituents selected from R ¹⁷ ;
[56] R ⁷ is hydrogen, C _1-4 alkyl, carbocyclic or heterocyclic, which is optionally substituted by one or more substituents selected from R ¹⁸ ;
[57] R ⁸ is hydrogen or C _1-4 alkyl;
[58] R ⁹ is hydrogen or C _1-4 alkyl;
[59] R ¹⁰ is hydrogen, C _1-4 alkyl, carbocyclic or heterocyclic, which is optionally substituted by one or more substituents selected from R ¹⁹ ;
[60] R ¹¹ is carboxy, sulfo, sulfino, phosphono, -P (O) (OR ^c ) (OR ^d ), -P (O) (OH) (OR ^c ), -P (O) (OH) (R ^d ) or —P (O) (OR ^c ) (R ^d ) wherein R ^c and R ^d are independently selected from C _1-6 alkyl, or R ¹¹ is a group of formula IB
[61] Formula IB
[62]
[63] Where Y is -N (R ^x )-, -N (R ^x ) C (O)-, -O-, and -S (O) a-, where a is 0-2 and R ^x is hydrogen or C _1-4 alkyl);
[64] R ¹² is hydrogen or C _1-4 alkyl;
[65] R ¹³ and R ¹⁴ are independently selected from hydrogen, C _1-6 alkyl, carbocyclic or heterocyclic, wherein R ¹³ and R ¹⁴ may be optionally substituted by one or more substituents selected from R ²⁰ ;
[66] R ¹⁵ is carboxy, sulfo, sulfino, phosphono, -P (O) (OR ^e ) (OR ^f ), -P (O) (OH) (OR ^e ),-P (O) (OH) (R ^e ) or -P (O) (OR ^e ) (R ^f ), where R ^e and R ^f are independently selected from C _1-6 alkyl:
[67] p is 1-3 (wherein the values of R ¹³ may be the same or different);
[68] q is 0 to 1;
[69] r is 0 to 3, wherein the value of R ¹⁴ may be the same or different;
[70] m is 0-2, wherein the value of R ¹⁰ may be the same or different;
[71] n is 1 to 3, wherein the value of R ⁷ may be the same or different;
[72] R ¹⁶ , R ¹⁷ and R ¹⁸ are independently halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-4 alkyl, C _2-4 alkenyl, C _{2 -4} alkynyl, C _1-4 alkoxy, C _1-4 alkanoyl, C _1-4 alkanoyloxy, N- (C _1-4 alkyl) amino, N, N- (C _1-4 alkyl) ₂ amino , C _1-4 alkanoylamino, N- (C _1-4 alkyl) carbamoyl, N, N- (C _1-4 alkyl) ₂ carbamoyl, C _1-4 alkylS (O) _a (where , a is 0-2, C _1-4 alkoxycarbonyl, N- (C _1-4 alkyl) sulfamoyl and N, N- (C _1-4 alkyl) ₂ sulfamoyl, wherein R ¹⁶ , R ¹⁷ and R ¹⁸ may independently be optionally substituted on carbon by one or more R ²¹ ;
[73] R ¹⁹ and R ²⁰ are independently halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alky Nyl, C _1-4 alkoxy, C _1-4 alkanoyl, C _1-4 alkanoyloxy, N- (C _1-4 alkyl) amino, N, N- (C _1-4 alkyl) ₂ amino, C _{1 -4} alkanoylamino, N- (C _1-4 alkyl) carbamoyl, N, N- (C _1-4 alkyl) ₂ carbamoyl, C _1-4 alkylS (O) _a where a is 0-2, C _1-4 alkoxycarbonyl, N- (C _1-4 alkyl) sulfamoyl and N, N- (C _1-4 alkyl) ₂ sulfamoyl, carbocyclic, heterocyclic, sulfo, sulfino, 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 C _1-6 alkyl, wherein R ¹⁹ and R ²⁰ may be independently substituted on carbon by one or more R ²² There will be;
[74] R ²¹ and R ²² are independently halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl , Ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N , N-dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl and N, N-dimethylsulfamoyl.]
[75] In this specification, the term "alkyl" includes both straight and branched chain alkyl groups, but references to individual alkyl groups such as "propyl" are specific only to the description of the straight chain. For example, "C _1-6 alkyl" includes C _1-4 alkyl, propyl, isopropyl and t-butyl. However, references to individual alkyl groups such as 'propyl' are only specific for the description of the straight chain and references to individual branched alkyl groups such as 'isopropyl' are only specific for the description of the branched chain. Similar rules apply to other radicals, for example "phenylC _1-6 alkyl" includes phenyl C _1-4 alkyl, benzyl, 1-phenylethyl and 2-phenylethyl. The term "halo" refers to fluoro, chloro, bromo and iodo.
[76] Where any substituent is selected from the groups "one or more", this definition is to be understood to include all substituents selected from one of the groups specified above or substituents selected from two or more of the groups specified above. do.
[77] "Heteroaryl" is a fully unsaturated, monocyclic or bicyclic ring containing 3 to 12 atoms selected from nitrogen, sulfur or oxygen, which may be carbon or nitrogen linked, unless otherwise indicated. Preferably, "heteroaryl" refers to a fully unsaturated, monocyclic ring containing 5 or 6 atoms selected from nitrogen, sulfur or oxygen, which may be carbon or nitrogen linked, unless otherwise specified Bicyclic rings containing 9 or 10 atoms. Examples and suitable meanings of the term “heteroaryl” are thienyl, isoxazolyl, imidazolyl, pyrroyl, thiadiazoleyl, isothiazolyl, triazolyl, pyranyl, indolyl, pyrimidyl, pyrazinyl, pyrida Genyl, pyridyl and quinolyl. Preferably, the term "heteroaryl" means thienyl or indolyl.
[78] "Aryl" is a fully unsaturated, monocyclic or bicyclic carbon ring containing 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 meanings for "aryl" are phenyl or naphthyl. In particular, "aryl" is phenyl.
[79] A "heterocycle" is a saturated, partially saturated or unsaturated monocyclic or bicyclic ring containing 3 to 12 atoms selected from nitrogen, sulfur or oxygen, which may be carbon or nitrogen linked, unless otherwise indicated. , Wherein -CH ₂ -group is optionally replaced with -C (O)-, or the ring sulfur atom can be optionally oxidized to form an S-oxide. Preferably, a "heterocycle" is a saturated, partially saturated or unsaturated monocyclic ring containing 5 or 6 atoms selected from nitrogen, sulfur or oxygen, which can be carbon or nitrogen linked, unless otherwise indicated. Or a bicyclic ring, wherein a -CH ₂ -group may be optionally substituted with -C (O)-, or a ring sulfur atom may be optionally oxidized to form an S-oxide. Examples and suitable meanings of the term “heterocycle” include thiazolidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidinyl, 2,5-dioxopyrrolidinyl, 2-benzoxazolininyl, 1,1- Dioxotetrahydrothienyl, 2,4-dioxoimidazolidinyl, 2-oxo-1,3,4- (4-triazolinyl), 2-oxazolidinononyl, 5,6-dihydrouracil 1,3-benzodioxolyl, 1,2,4-oxadiazolyl, 2-azabicyclo [2.2.1] heptyl, 4-thiazolidonyl, morpholino, 2-oxotetrahydrofuranyl, Tetrahydrofuranyl, 2,3-dihydrobenzofuranyl, benzothienyl, tetrahydropyranyl, piperidyl, 1-oxo-1,3-dihydroisoindolyl, piperazinyl, thiomorpholino , 1,1-dioxothiomorpholino, tetrahydropyranyl, 1,3-dioxolanyl, homopiperazinyl, thienyl, isoxazolyl, imidazolyl, pyrrolyl, thiadiazolyl, isothia Zolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, pyranyl, indolyl, pyrimi Dill, thiazolyl, pyrazinyl, pyridazinyl, pyridyl, 4-pyridonyl, quinolyl and 1-isoquinoloyl.
[80] A "carbocyclic ring" is a saturated, partially saturated or unsaturated monocyclic or bicyclic carbon ring containing 3 to 12 atoms, wherein the -CH ₂ -group may be optionally replaced by -C (O)-. Preferably, a "carbocyclic ring" is a monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms. Suitable examples of "carbocyclic ring" include cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl, tetralinyl, indanyl or 1-oxoindanyl It includes. In particular, a "carbocyclic ring" is cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl or 1-oxoindanyl.
[81] Examples of "C _1-6 alkanoyloxy" and "C _1-4 alkanoyloxy" are acetoxy. Examples of "C _1-6 alkoxycarbonyl" and "C _1-4 alkoxycarbonyl" include methoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl. Examples of “C _1-6 alkoxy” and “C _1-4 alkoxy” include methoxy, ethoxy and propoxy. Examples of "C _1-6 alkanoylamino" and "C _1-4 alkanoylamino" include formamido, acetamido and propionylamino. Examples of "C _1-6 alkyl S (O) _a (where a is 0-2)" and "C _1-4 alkyl S (O) _a (where a is 0-2)" include methylthio, ethyl Thio, methylsulfinyl, ethylsulfinyl, mesyl and ethylsulfonyl. Examples of “C _1-6 alkanoyl” and “C _1-4 alkanoyl” include propionyl and acetyl. Examples of "NC _1-6 alkylamino" and "NC _1-4 alkylamino" include methylamino and ethylamino. Examples of "N, N- (C _1-6 alkyl) ₂ amino" and "N, N- (C _1-4 alkyl) ₂ amino" include di-N-methylamino, di- (N-ethyl) amino and N-ethyl-N-methylamino is included. Examples of "C _2-6 alkenyl" and "C _2-4 alkenyl" are vinyl, allyl and 1-propenyl. Examples of "C _2-6 alkynyl" and "C _2-4 alkynyl" are ethynyl, 1-propynyl and 2-propynyl. Examples of "N- (Ci _-6 alkyl) sulfamoyl" and "N- (Ci _-4 alkyl) sulfamoyl" are N- (methyl) sulfamoyl and N- (ethyl) sulfamoyl. Examples of "N- (C _1-6 alkyl) ₂ sulfamoyl" and "N- (C _1-4 alkyl) ₂ sulfamoyl" are N, N- (dimethyl) sulfamoyl and N- (methyl) -N- (Ethyl) sulfamoyl. Examples of "N- (C _1-6 alkyl) carbamoyl" and "N- (C _1-4 alkyl) carbamoyl" are methylaminocarbonyl and ethylaminocarbonyl. Examples of "N, N- (Ci _-6 alkyl) ₂ carbamoyl" and "N, N- (Ci _-4 alkyl) ₂ carbamoyl" are dimethylaminocarbonyl and methylethylaminocarbonyl. Examples of “(C _1-4 alkyl) ₃ silyl” are trimethylsilyl and methyldiethylsilyl.
[82] Suitable pharmaceutically acceptable salts of the compounds of the invention are, for example, acid addition salts of the compounds of the invention which are sufficiently basic, for example inorganic or organic acids, for example hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, trifluoric acid. Acid addition salts with roacetic acid, citric acid, acetic acid or maleic acid. In addition, suitable pharmaceutically acceptable salts of the compounds of the present invention that are sufficiently acidic provide alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, ammonium salts, or physiologically acceptable cations. Salts with organic bases such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris- (2-hydroxyethyl) amine.
[83] Compounds of formula (I) may be administered in the form of prodrugs that degrade in the human or animal body to provide compounds of formula (I). Examples of prodrugs include in vivo hydrolyzable esters of compounds of formula (I) and in vivo hydrolyzable amides.
[84] In vivo hydrolyzable esters of compounds of formula (I) containing carboxyl or hydroxy groups are, for example, pharmaceutically acceptable esters which are hydrolyzed in the body of a human or animal to produce a parent acid or a moal alcohol. . Suitable pharmaceutically acceptable esters for carboxy include C _1-6 alkoxymethyl esters such as methoxymethyl; C _-6 alkanoyloxymethyl esters such as pivaloyloxymethyl, phthalidyl esters; C _3-8 cycloalkoxycarbonyloxy C _1-6 alkyl esters such as 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolene-2-onylmethyl esters such as 5-methyl-1,3-dioxolene-2-onylmethyl and Cl _-6 alkoxycarbonyloxyethyl esters such as 1-methoxy Carbonyloxyethyl is included and may be formed at any carboxyl group in the compounds of the present invention.
[85] In vivo hydrolyzable esters of compounds of formula (I) containing hydroxy groups include inorganic esters such as phosphate esters and α-acyloxyalkyl ethers and as a result of in vivo hydrolysis of such esters to provide parent hydroxy groups. Related compounds. Examples of α-acyloxyalkyl ethers are acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy. Selection of in vivo hydrolyzable ester forming groups for hydroxy includes alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (which provides alkyl carbonate esters), dialkylcarbamoyl and N- (Dialkylaminoethyl) -N-alkylcarbamoyl (which provides carbamate), dialkylaminoacetyl and carboxyacetyl. Examples of substituents on benzoyl include piperazino and morpholino bonded to the 3 or 4 position of the benzoyl ring from the ring nitrogen atom via a methylene group.
[86] Suitable examples of hydrolyzable amides in vivo of compounds of formula I containing carboxyl groups are, for example, N-methyl, N-ethyl, N-propyl, N, N-dimethyl, N-ethyl-N-methyl or NC _1-6 alkyl or N, N-di-C _1-6 alkyl amide, such as N, N-diethyl amide.
[87] Some compounds of formula (I) may have chiral centers and / or geometric isomeric centers (E- and Z-isomers), and the present invention includes all geometric isomers, diastereomers and optical isomers having IBAT inhibitory activity. It must be understood.
[88] The present invention relates to any and all tautomers of the compounds of formula (I) above which are IBAT inhibitory activities.
[89] In addition, certain compounds of formula (I) may exist as solvated as well as unsolvated, such as, for example, hydrated. It is to be understood that the present invention includes all these solvated forms that are IBAT inhibitory activity.
[90] Specific examples are as follows. Such examples may be suitably used in any of the definitions, claims, or embodiments defined above or below.
[91] R ¹ and R ² are C _1-4 alkyl.
[92] R ¹ and R ² are butyl.
[93] ^One of R ¹ and R ² is ethyl and the other is butyl.
[94] ^One of R ¹ and R ² is ethyl and the other is butyl or R ¹ and R ² are both butyl.
[95] v is 0 or 1;
[96] v is zero.
[97] R ^z is C _1-4 alkyl.
[98] R ^y is hydrogen.
[99] R ^y is hydrogen or hydroxy.
[100] R ³ and R ⁶ are hydrogen.
[101] R ⁴ is methylthio.
[102] R ⁴ is hydrogen.
[103] R ⁴ is hydrogen, halo or C _1-4 alkylS (O) _a , where a is 0.
[104] R ⁴ is hydrogen, bromo, methylthio.
[105] R ⁵ is a group of formula IA (as shown above) wherein:
[106] X is -O-;
[107] n is 1;
[108] R ⁷ is hydrogen;
[109] R ⁸ is hydrogen;
[110] R ⁹ is hydrogen;
[111] m is 0;
[112] R ¹¹ is carboxy.
[113] R ⁵ is N-((R) -α-carboxybenzyl) carbamoylmethoxy.
[114] R ⁵ is a group of formula IA (as shown above) wherein:
[115] X is -O-;
[116] Ring A is aryl (ring A is optionally substituted with one or more substituents selected from R ¹⁷ );
[117] R ⁷ is hydrogen;
[118] R ⁸ is hydrogen;
[119] R ⁹ is hydrogen;
[120] R ¹¹ is carboxy or a group of formula IB (as shown above) wherein:
[121] R ¹² is hydrogen;
[122] R ¹³ is hydrogen;
[123] R ¹⁵ is carboxy or sulfo;
[124] p is 1 or 2;
[125] q is 0;
[126] r is 0;
[127] m is 0;
[128] n is 1;
[129] R ¹⁷ is hydroxy.
[130] R ⁵ is a group of formula IA (as shown above) wherein:
[131] X is -O-;
[132] Ring A is phenyl or 4-hydroxyphenyl;
[133] R ⁷ is hydrogen;
[134] R ⁸ is hydrogen;
[135] R ⁹ is hydrogen;
[136] R ¹¹ is carboxy or a group of formula IB (as shown above) wherein:
[137] R ¹² is hydrogen;
[138] R ¹³ is hydrogen;
[139] R ¹⁵ is carboxy or sulfo;
[140] p is 1 or 2;
[141] q is 0;
[142] r is 0;
[143] m is 0;
[144] n is 1;
[145] R ⁵ is N-((R) -α-carboxybenzyl) carbamoylmethoxy; N-{(R) -α- [N- (carboxymethyl) carbamoyl] benzyl} carbamoylmethoxy or N-{(R) -α- [N- (2-sulfoethyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy.
[146] Thus, in one aspect of the invention,
[147] R ¹ and R ² are C _1-4 alkyl.
[148] v is zero.
[149] R ^y is hydrogen or hydroxy.
[150] R ³ and R ⁶ are hydrogen.
[151] R ⁴ is hydrogen, halo or C _1-4 alkylS (O) _a , where a is 0.
[152] R ⁵ is a group of formula IA (as shown above) wherein:
[153] X is -O-;
[154] Ring A is aryl (ring A is optionally substituted with one or more substituents selected from R ¹⁷ );
[155] R ⁷ is hydrogen;
[156] R ⁸ is hydrogen;
[157] R ⁹ is hydrogen;
[158] R ¹¹ is carboxy or a group of formula IB (as shown above) wherein:
[159] R ¹² is hydrogen;
[160] R ¹³ is hydrogen;
[161] R ¹⁵ is carboxy or sulfo;
[162] p is 1 or 2;
[163] q is 0;
[164] r is 0;
[165] m is 0;
[166] n is 1;
[167] R ¹⁷ is hydroxy
[168] Or a pharmaceutically acceptable salt, solvate, solvate or prodrug of such salts thereof.
[169] Thus, in one aspect of the invention,
[170] One of R ¹ and R ² is ethyl and the other is butyl;
[171] v is 0;
[172] R ^y is hydrogen or hydroxy;
[173] R ³ and R ⁶ are hydrogen;
[174] R ⁴ is hydrogen, bromo or methylthio;
[175] R ⁵ is N-((R) -α-carboxybenzyl) carbamoylmethoxy; N-{(R) -α- [N- (carboxymethyl) carbamoyl] benzyl} carbamoylmethoxy or N-{(R) -α- [N- (2-sulfoethyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy
[176] Or a pharmaceutically acceptable salt, solvate, solvate or prodrug of such salts thereof.
[177] In another aspect of the invention, the preferred compounds of the invention are any one of the embodiments or pharmaceutically acceptable salts, solvates, solvates or prodrugs of such salts.
[178] Preferred aspects of the invention relate to compounds of formula (I) or pharmaceutically acceptable salts thereof.
[179] Another aspect of the invention provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, wherein the group is used unless otherwise indicated. As defined in formula (I) includes any one of the following methods 1) to 10) and then includes the following i) to iii) if necessary or desired:
[180] Method 1) A method of oxidizing benzothiazepine of formula II:
[181]
[182] Method 2) For compounds of formula I, wherein X is -O-, -NR ^a or -S-, the method of reacting a compound of formula IIIa or IIIb with a compound of formula IV:
[183]
[184]
[185]
[186] In the above formula, L is a substitutable group
[187] Method 3): A method of reacting an acid of formula Va or Vb or an active derivative thereof with an amine of formula VI:
[188]
[189]
[190]
[191] Method 4): For compounds of formula (I), in which R ¹¹ is a group of formula (IB), a method of reacting a compound of formula (I) wherein R ¹¹ is carboxyl with an amine
[192]
[193] Method 5) For compounds of formula I, wherein R ¹¹ is a group of formula IB and R ¹⁵ is a group of formula IC, the compound of formula I wherein R ¹⁵ is carboxyl is reacted with an amine of formula VIII:
[194]
[195] Method 6): For compounds of formula I wherein one of R ⁴ and R ⁵ is independently selected from C _1-6 alkylthio optionally substituted with one or more R ¹⁶ on carbon, the compound of formula IXa or IXb is Reaction with thiol of X:
[196]
[197]
[198] R ^m -H
[199] In the above formula, L is a substitutable group and R ^m is C _1-6 alkylthio optionally substituted with one or more R ¹⁶ on carbon.
[200] Method 7) For compounds of formula I, wherein R ¹¹ is carboxy, the method for deprotecting a compound of formula XIa or XIb:
[201]
[202]
[203] In the above formula, R ^x forms an ester with the —OC (O) — group to which it is attached
[204] Method 8): For compounds of formula I, wherein R ¹¹ is a group of formula IB and R ¹⁵ is carboxy, the method for deprotecting a compound of formula XIIa or XIIb:
[205]
[206]
[207] In the above formula, R ^x forms an ester with the —OC (O) — group to which it is attached
[208] Method 9): For compounds of formula I, wherein R ¹¹ is a group of formula IB and Y is -N (R ^x ) C (O)-, an acid of formula XIIIa or XIIIb or an active derivative thereof Reaction with amines:
[209]
[210]
[211]
[212] Or method 10) for compounds of formula I, wherein R ¹¹ is a group of formula IB, R ¹⁵ is a group of formula IC, and R ²⁶ is carboxy, a method for deprotecting a compound of formula XVa or XVb:
[213]
[214]
[215] In the above formula, R ^x forms an ester with the —OC (O) — group to which it is attached
[216] i) converting a compound of formula (I) to another compound of formula (I);
[217] ii) removing any protecting group;
[218] iii) a method of forming a pharmaceutically acceptable salt, solvate, solvate or prodrug of said salt.
[219] L is a substitutable group and suitable examples for L are, for example, halogeno or sulfonyloxy groups such as chloro, bromo, methanesulfonyloxy or toluene-4-sulfonyloxy groups.
[220] R ^x together with the —OC (O) — group to which it is attached form an ester. R ^p is preferably methyl or ethyl. More preferably, R ^x is methyl. In another aspect of the invention, R ^x is C _1-6 alkyl or phenylC _1-6 alkyl, preferably C _1-4 alkyl or benzyl, more preferably t-butyl, methyl, ethyl or benzyl.
[221] Specific reaction conditions for the reaction are as follows:
[222] Method 1) The benzothiazepines of formula (II) may be oxidized under standard sulfur oxidation conditions, for example using hydrogen peroxide and trifluoroacetic acid at temperatures ranging from 0 ° C. to reflux, preferably near room temperature.
[223] Compounds of Formula II may be prepared according to Scheme I:
[224]
[225] Compounds of formula (IIa), (IIb) and (IIf) are commercially available compounds or are prepared by standard methods known in the literature or known in the art.
[226] Method 2): The compound of formula IIIa or IIIb is in the presence of a suitable solvent such as acetonitrile, dichloromethane or tetrahydrofuran in the range of 0 ° C. to reflux temperature, preferably near reflux temperature, for example an inorganic base such as sodium carbonate Or in the presence of an organic base such as the Hunigs base.
[227] Compounds of formula IIIa or IIIb may be prepared in a similar manner to compounds of formula II (wherein R ⁴ or R ⁵ is —OH, —NH (R ^a ) or —SH, followed by the oxidation step of method 1 ). In addition, compounds of formula IIIa or IIIb (X being -OR or -NR ^a ) may be prepared by the procedure of WO 96/08484 or WO 98/40375.
[228] Compounds of formula IV are commercially available compounds or are prepared by standard methods known in the literature or known in the art.
[229] Methods 3) and Methods 4) and Methods 5) and Methods 9): Acids and amines may be coupled together in the presence of a suitable coupling reagent. Optionally in the presence of a catalyst such as dimethylaminopyridine or 4-pyrrolidinopyridine, optionally for example triethylamine, pyridine or 2,6-di-alkyl-pyridine, such as 2,6-lutidine or 2,6- Standard peptide coupling reagents known in the art in the presence of a base such as di-t-butylpyridine can be used as suitable coupling reagents, for example carbonyldiimidazole and dicyclohexyl-carbodiimide. Suitable solvents include dimethylacetamide, dichloromethane, benzene, tetrahydrofuran and dimethylformamide. It may be convenient for the coupling reagent to be carried out at a temperature in the range of -40 to 40 ° C.
[230] Suitable activated acid derivatives include acid halides such as acid chlorides and active esters such as pentafluorophenyl esters. The reaction of these types of compounds with amines is known in the art and for example they may be reacted in a suitable solvent as described above in the presence of a base as described above. It may be convenient to carry out the reaction at a temperature in the range of -40 to 40 ° C.
[231] Compounds of formula Va or Vb, wherein X is -O-, -NR ^a or -S-, may be prepared according to Scheme 2:
[232]
[233] L in formulas (IXa) and (IXb) is a substitutable group such as bromo, chloro, fluoro, mesyl or tosyl, and X is -O-, -S-, NR ^a (optionally -SO- and -SO ₂ Is followed by the oxidation step of Method 1).
[234] Compounds of formulas Va and Vb in which X is —SO— or —SO ₂ — may be prepared by oxidizing the resulting compounds of formulas Va and Vb from Scheme 2 where X is —S—.
[235] Compounds of formula Va or Vb wherein X is —CH ₂ — and n is 1 may be prepared according to Scheme 3 below.
[236]
[237] Those skilled in the art will appreciate that the scheme can be manipulated to produce compounds of formula Va or Vb wherein n is 2 or 3.
[238] Compounds of formula (XIIIa) and (XIIIb) may be prepared by manipulations known to those skilled in the art of the methods described herein.
[239] Compounds of formula (Vc), (VI), (VII), (VIII) and (XIV) are commercially available compounds, or they are known in the literature, or they are prepared by standard methods known in the art.
[240] Method 6): The compounds of formulas IXa and IXb range from 0 ° C. to reflux in the presence of a base, for example an inorganic base such as sodium carbonate or an organic base such as Hunigs base, in the presence of a suitable solvent, for example DMF or THF. It may be reacted with a thiol of formula X at the temperature of.
[241] Compounds of formula (IXa) and (IXb) may be prepared by any of the above procedures for the preparation of compounds of formula (I), but one of R ⁴ and R ⁵ is L.
[242] Compounds of formula (X) are commercially available compounds, or they are known in the literature, or they are prepared by standard procedures known in the art.
[243] Methods 7) and 8): Method 10): Esters of formulas XIa, XIb, XIIa, XIIb, XVa and XVb may be deprotected using standard conditions as follows, e.g. in methanol at room temperature It may be deprotected with sodium hydroxide.
[244] Esters of formulas (XIa), (XIb), (XIIa), (XIIb) (XVa) and (XVb) may be prepared by any of the above procedures for the preparation of compounds of formula (I), but R ¹⁵ or R ²⁶ are esters.
[245] It is recognized that certain of the various ring substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications prior to or immediately after the methods described above, and such may be included in the features of the process of the invention. Will be done. These reactions and modifications include introduction of substituents by means of, for example, aromatic substitution reactions, reduction of substituents, alkylation of substituents and oxidation of substituents. Reagents and reaction conditions for these methods are known in the chemical art. Specific examples of the aromatic substitution reaction include introduction of nitro groups using concentrated nitric acid, for example, acyl halides and acyl groups using Lewis acids (eg, aluminum trichloride) under Friedel Kraft conditions, and halogeno groups. There is an introduction. Specific examples of modification include, for example, catalytic hydrogenation with a nickel catalyst or reduction of nitro groups to amino groups by iron treatment in the presence of heated hydrochloric acid and alkylthio to alkylsulfinyl or alkylsulfonyl. There is oxidation.
[246] It will also be appreciated that in some of the reactions mentioned herein it may be necessary or desirable to protect any sensitive groups in the compound. Examples that require or require protection and appropriate methods for protection are known to those skilled in the art. Conventional protecting groups can be used according to standard practice (see, eg, T.W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Thus, when the reactants include groups such as amino, carboxy or hydroxy, it may be desirable to protect the groups in some of the reactions mentioned herein.
[247] Examples of suitable protecting groups for amino groups or alkylamino groups include acyl groups, for example alkanoyl groups such as acetyl, alkoxycarbonyl groups, for example methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl groups, arylmethoxycarbonyl groups For example benzyloxycarbonyl, or aroyl groups such as benzoyl. The deprotection conditions for the protecting group necessarily depend on the choice of protecting group. Thus, for example, acyl or aroyl groups such as alkanoyl or alkoxycarbonyl groups can be removed by hydrolysis with a suitable base such as alkali metal hydroxides such as lithium hydroxide or sodium hydroxide. Alternatively, acyl groups such as t-butoxycarbonyl groups can be removed by treatment with, for example, hydrochloric acid, sulfuric acid or a suitable acid such as phosphoric acid or trifluoroacetic acid, and arylmethoxycarbonyl groups such as benzyloxycarbonyl groups, for example For example, it can be removed by hydrogenation in the presence of a catalyst such as palladium on carbon or by treatment of a Lewis acid such as bromine tris (trifluoroacetate). Suitable alternative protecting groups for the first amino group are, for example, phthaloyl groups which can be removed by treatment with an alkylamine or hydrazine such as dimethylaminopropylamine.
[248] Examples of suitable protecting groups for hydroxy groups are acyl groups such as alkanoyl groups such as acetyl, aroyl groups such as benzoyl or arylmethyl groups such as benzyl. The deprotection conditions for the protecting group necessarily depend on the choice of protecting group. Thus, for example, acyl groups such as aroyl groups or alkanoyl groups can be removed by hydrolysis with an appropriate base such as, for example, alkali metal hydroxides, for example lithium hydroxide or sodium hydroxide. Alternatively, the arylmethyl group, such as the benzyl group, can be removed by hydrogenation, for example in the presence of a catalyst such as palladium on carbon.
[249] Examples of suitable protecting groups for carboxyl groups are, for example, methyl or ethyl groups, which can be removed by hydrolysis with an esterification group, for example sodium hydroxide, or an organic acid, for example trifluoroacetic acid. There are t-butyl groups that can be removed by treatment of the acid, or benzyl groups that can be removed by hydrogenation in the presence of a catalyst such as, for example, palladium on carbon.
[250] The protecting group can be removed in a convenient way of the synthetic seam using conventional techniques well known in the chemical art.
[251] As mentioned above, the compounds defined in the present invention have IBAT inhibitory activity. These properties can be used, for example, using in vitro test assays to study the effect of bile acid intake in IBAT-infected cells (Smith L., Price-Jones MJ, Hugnes KT and Jones NRA; J. Biomolecular Screening, 3, 227-230), or by studying the effect of radiolabeled bile uptake in mice / rats in vivo (Lewis MC, Brieaddy LE and Root C., J., J Lip Res 1995, 36, 1098-). 1105).
[252] According to another aspect of the invention, a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, together with a pharmaceutically acceptable diluent or carrier A pharmaceutical composition is provided.
[253] The compositions of the present invention may be used, for example, for oral administration as tablets or capsules, for parenteral administration as sterile solutions, suspensions or emulsions (including, for example, intravenous, subcutaneous, intramuscular, intravascular or inhaled), ointments or Formulations suitable for topical administration as a cream or for enteral administration as suppositories.
[254] In general, the compositions of the present invention can be obtained by conventional procedures using conventional excipients.
[255] Generally, compounds of formula (I), or pharmaceutically acceptable salts, solvates, solvates or prodrugs thereof, range from 5 to 5000 mg per m ² of body area of the animal, ie from about 0.02 to It is administered at a unit dose of 100 mg / kg, preferably 0.02-50 mg / kg, which provides a conventional therapeutically effective dosage. Usually, unit dosage forms such as tablets or capsules contain, for example, 1 to 250 mg of the active ingredient. The daily dosage is preferably used in the range from 1 to 50 mg / kg, especially in the range from 0.1 to 10 mg / kg. However, the daily dosage will necessarily depend on the host to be treated, the particular route of administration and the severity of the disease to be treated. Thus, the optimal dosage can be determined by the practitioner treating any particular patient.
[256] According to another aspect of the invention, a compound of formula (I), a pharmaceutically acceptable salt, solvate, solvent of said salt, as defined above, for use in a method of prophylactic or therapeutic treatment of a warm blooded animal such as a human Freight or prodrug is provided.
[257] The inventors have found that the compounds defined in the present invention, their pharmaceutically acceptable salts, solvates, solvates or prodrugs of such salts are effective IBAT inhibitors and are therefore valuable for the treatment of disease states associated with hyperlipidemic conditions. It was.
[258] Accordingly, according to this aspect of the invention there is provided a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, for use as a medicament.
[259] According to another aspect of the invention, a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, solvate thereof, in the manufacture of a medicament for use in producing an IBAT inhibitory effect in a warm blooded animal such as a human The use of solvates or prodrugs of such salts is provided.
[260] According to another aspect of the invention, a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, solvate, or salt thereof, in the manufacture of a medicament for the treatment of hyperlipidemic conditions in a warm blooded animal such as a human The use of solvates or prodrugs is provided.
[261] Another aspect of the invention is a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, solvent thereof, as described above in the manufacture of a medicament for use in generating an IBAT inhibitory effect in warm blooded animals such as humans. The use of a cargo, solvate or prodrug of said salt is provided.
[262] When described herein as "generating the IBAT inhibitory effect" or "generating the IBAT inhibitory effect", this refers in particular to the treatment of hyperlipidemic conditions. In another aspect, "generating the IBAT inhibitory effect" or "generating the IBAT inhibitory effect" includes hyperlipidemia, hypertriglyceridemia, hyperbetalipoproteinemia (high LDL), classical betaproteinemia (high VLDL), adiposity lipidemia And treatment of abnormal hemostatic conditions and diseases such as hypolipoproteinemia, hypercholesterolemia, hyperlipoproteinemia and hypoalphalipoproteinemia (low HDL). In another aspect, "generating the IBAT inhibitory effect" or "generating the IBAT inhibitory effect" means atherosclerosis, atherosclerosis, arrhythmia, hyperthrombotic state, vascular insufficiency, endothelial insufficiency, heart failure, coronary heart disease, cardiovascular disease , Myocardial infarction, angina pectoris, peripheral vascular disorders, cardiovascular tissues such as inflammation of the heart, valves, blood vessels, arteries and veins, aneurysms, stenosis, restenosis, blood spots, vascular adipocytes, leukocytes, monocytes and / or macrophage infiltration , Endometrial thickening, medial thinning, infection and treatment of different clinical conditions such as trauma and thrombosis, stroke and transient ischemic attacks. In another aspect, "generating the IBAT inhibitory effect" or "generating the IBAT inhibitory effect" refers to the treatment of atherosclerosis, coronary heart disease, myocardial infarction, angina pectoris, peripheral vascular disorders, stroke and transient ischemic attack.
[263] In another aspect of the invention, the invention provides a method for generating an IBAT inhibitory effect in a warm blooded animal such as a human, comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, solvate or pro Provided is a method comprising administering a drug to the animal.
[264] In another aspect of the invention, the invention provides a method of treating a hyperlipidemic condition in a warm blooded animal, such as a person in need thereof, comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, solvent of said salt Provided is a method comprising administering a cargo or prodrug to said animal.
[265] The dosage size required for a therapeutic or prophylactic treatment necessarily depends on the host being treated, the route of administration and the severity of the condition to be treated. The unit dosage range is, for example, 0.1 to 50 mg / kg, preferably 0.1 to 10 mg / kg is contemplated.
[266] The IBAT inhibitory activity as defined above may be applied as a single treatment or may comprise one or more other substances and / or treatments in addition to the compounds of the invention. Such co-treatment can be achieved by simultaneous, continuous or separate modes of administration of the individual components to be treated. According to this aspect of the invention there is provided a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, as well as further IBAT inhibitors as defined above and There is provided a pharmaceutical composition comprising an additional hypolipidemic agent for the combined treatment of hyperlipidemia.
[267] In another aspect of the invention, the compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, may be a HMG Co-A reductase inhibitor, or a pharmaceutically acceptable It may be administered with a salt, solvate, solvate or prodrug of the salt. Suitable HMG Co-A reductase inhibitors, pharmaceutically acceptable salts, solvates, solvates or prodrugs of such salts are statins well known in the art. Specific statins are fluvastatin, lovastatin, pravastatin, simvastatin, atorvastatin, cerivastatin, vervastatin, dalvastatin mevastatan, medivastatin and (E) -7- [4- (4-fluorophenyl)- 6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3R, 5S) -3,5-dihydroxyhept-6-enoic acid (rosuvastatin), or theirs Pharmaceutically acceptable salts, solvates, solvates or prodrugs of such salts. Particular statins are atorvastatin, or pharmaceutically acceptable salts, solvates, solvates or prodrugs of these salts. More particular statin is atorvastatin calcium salt. Even more specific statins are (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3R, 5S) -3,5-dihydroxyhept-6-enoic acid, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof.
[268] In a further aspect of the invention, the compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, is an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt thereof. Administration with solvates, solvates or prodrugs of the salts and / or bile acid binders may avoid the risk of excess bile acid in the colon caused by inhibition of the ileal bile acid transport system. Excess bile acids in the intestinal contents can cause diarrhea. Accordingly, the present invention also provides for the treatment of possible side effects such as diarrhea in a patient during treatment comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof.
[269] HMG Co-A reductase inhibitors, or pharmaceutically acceptable salts, solvates, solvates or prodrugs thereof, reduce the endogenous cholesterol that can be used for bile acid synthesis by their action, Or, in combination with their pharmaceutically acceptable salts, solvates, solvates or prodrugs of such salts, has a further effect on lipid reduction.
[270] Suitable bile acid binders for such combination therapies are resins such as cholestyramine and cholisnipol. One advantage is that the dose of bile acid binder can be kept lower than the therapeutic dose for treating hypercholesterolemia in a monotherapy comprising only bile acid binder. In addition, any possible side effects caused by poor tolerance of the patient to the therapeutic dose by the lower dose of bile acid binders can be avoided.
[271] Thus, in a further aspect of the invention, an effective amount of HMG Co-A is reduced in an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, to a warm blooded animal such as a human A method for producing an IBAT inhibitory effect in an animal in need of such treatment, comprising simultaneously, sequentially or separately administering an enzyme inhibitor, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof. This is provided.
[272] Thus, in a further aspect of the invention, an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, in a warm blooded animal, such as a human, is simultaneously, sequentially or A method is provided for producing an IBAT inhibitory effect in an animal in need of treatment, comprising the step of administering separately.
[273] Thus, in a further aspect of the invention, an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, solvate of said salt, in simultaneous, sequential or separate administration with a bile acid binder to a warm blooded animal such as a human Or administering the prodrug concurrently, sequentially or separately with an effective amount of an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof. A method is provided for producing an IBAT inhibitory effect in an animal.
[274] Thus, in a further aspect of the invention, an effective amount of HMG Co-A is reduced in an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, to a warm blooded animal such as a human Methods are provided for treating hyperlipidemia in an animal in need of treatment, including simultaneous, sequential or separate administration of an enzyme inhibitor, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof.
[275] Thus, in a further aspect of the invention, an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, in a warm blooded animal such as a human is simultaneously administered with an effective amount of a bile acid binder, Methods of treating hyperlipidemia in animals in need of treatment, including sequential or separate administration, are provided.
[276] Thus, in a further aspect of the invention, an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, solvate of said salt, in simultaneous, sequential or separate administration with a bile acid binder to a warm blooded animal such as a human Or administering the prodrug concurrently, sequentially or separately with an effective amount of an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof. Methods of treating hyperlipidemia in animals are provided.
[277] According to another aspect of the invention, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug of said salt and HMG Co-A reductase inhibitor, or a pharmaceutically acceptable thereof Pharmaceutical compositions are provided which contain possible salts, solvates, solvates or prodrugs of such salts with pharmaceutically acceptable diluents or carriers.
[278] According to another aspect of the invention, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug of said salt and bile acid binder is contained together with a pharmaceutically acceptable diluent or carrier Pharmaceutical compositions are provided.
[279] According to another aspect of the invention, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, HMG Co-A reductase inhibitor, or a pharmaceutically acceptable thereof Pharmaceutical compositions are provided which contain possible salts, solvates, solvates or prodrugs of such salts, and bile acid binders with pharmaceutically acceptable diluents or carriers.
[280] According to another aspect of the invention, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug of said salt and HMG Co-A reductase inhibitor, or a pharmaceutically acceptable thereof Kits are provided which comprise possible salts, solvates, solvates or prodrugs of such salts.
[281] According to another aspect of the invention, there is provided a kit comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug of said salt, and a bile acid binder.
[282] According to another aspect of the invention, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, HMG Co-A reductase inhibitor, or a pharmaceutically acceptable thereof Kits are provided which include possible salts, solvates, solvates or prodrugs of such salts, and bile acid binders.
[283] According to another aspect of the invention, there is provided a kit comprising the following a) to c):
[284] a) a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, of a first unit dosage form;
[285] b) HMG Co-A reductase inhibitor of the second unit dosage form, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof; And
[286] c) container means for containing said first and second formulations.
[287] According to another aspect of the invention, there is provided a kit comprising the following a) to c):
[288] a) a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, of a first unit dosage form;
[289] b) bile acid binder in a second unit dosage form; And
[290] c) container means for containing said first and second formulations.
[291] According to another aspect of the invention, there is provided a kit comprising the following a) to d):
[292] a) a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, of a first unit dosage form;
[293] b) HMG Co-A reductase inhibitor of the second unit dosage form, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof;
[294] c) bile acid binder in a third unit dosage form; And
[295] d) container means for containing said first, second and third formulations.
[296] According to another aspect of the invention, there is provided a kit comprising the following a) to c):
[297] a) a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug of said salt, and a pharmaceutically acceptable diluent or carrier thereof, in a first unit dosage form;
[298] b) HMG Co-A reductase inhibitor of the second unit dosage form, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof; And
[299] c) container means for containing said first and second formulations.
[300] According to another aspect of the invention, there is provided a kit comprising the following a) to c):
[301] a) a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug of said salt, and a pharmaceutically acceptable diluent or carrier thereof, in a first unit dosage form;
[302] b) bile acid binder in a second unit dosage form; And
[303] c) container means for containing said first and second formulations.
[304] According to another aspect of the invention, there is provided a kit comprising the following a) to d):
[305] a) a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug of said salt, and a pharmaceutically acceptable diluent or carrier thereof, in a first unit dosage form;
[306] b) HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, in a second unit dosage form;
[307] c) bile acid binder in a third unit dosage form; And
[308] d) container means for containing said first, second and third formulations.
[309] According to another aspect of the present invention, in the preparation of a medicament for generating an IBAT inhibitory effect in a warm blooded animal such as a human, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of said salt or Provided are prodrugs and HMG Co-A reductase inhibitors, or pharmaceutically acceptable salts, solvates, solvates or prodrugs of these salts.
[310] According to another aspect of the present invention, in the preparation of a medicament for generating an IBAT inhibitory effect in a warm blooded animal such as a human, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of said salt or The use of prodrugs and bile acid binders is provided.
[311] According to another aspect of the invention, in the preparation of a medicament for generating an IBAT inhibitory effect in a warm blooded animal such as a human, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of said salt or The use of prodrugs, HMG Co-A reductase inhibitors, or pharmaceutically acceptable salts, solvates, solvates or prodrugs of these salts and bile acid binders is provided.
[312] According to another aspect of the invention, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, in the manufacture of a medicament for the treatment of hyperlipidemia in a warm blooded animal such as a human And HMG Co-A reductase inhibitors, or their pharmaceutically acceptable salts, solvates, solvates or prodrugs of such salts.
[313] According to another aspect of the invention, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of said salt, in the manufacture of a medicament for the treatment of hyperlipidemic conditions in warm-blooded animals such as humans, or The use of prodrugs and bile acid binders is provided.
[314] According to another aspect of the invention, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, in the manufacture of a medicament for the treatment of hyperlipidemia in a warm blooded animal such as a human , HMG Co-A reductase inhibitors, or pharmaceutically acceptable salts, solvates, solvates or prodrugs of such salts and the use of bile acid binders are provided.
[315] According to another aspect of the invention, an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, and optionally a warm blooded animal, such as a person in need of therapeutic treatment, and optionally A pharmaceutically acceptable diluent or carrier may be used in combination with an effective amount of an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, and optionally a pharmaceutically acceptable diluent or carrier. Combination therapies comprising the simultaneous, sequential or separate administration are provided.
[316] According to another aspect of the invention, an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, and optionally a warm blooded animal, such as a person in need of therapeutic treatment, and optionally Combination therapies are provided comprising administering a pharmaceutically acceptable diluent or carrier concurrently, sequentially or separately with an effective amount of a bile acid binder and optionally a pharmaceutically acceptable diluent or carrier.
[317] According to another aspect of the invention, an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, and optionally a warm blooded animal, such as a person in need of therapeutic treatment, and optionally Concurrent pharmaceutically acceptable diluents or carriers with an effective amount of an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, and optionally a pharmaceutically acceptable excipient. Combination therapy comprising administering sequentially, separately or concurrently, sequentially or separately with an effective amount of a bile acid binder and optionally a pharmaceutically acceptable diluent or carrier is provided.
[318] According to another aspect of the invention, an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, of a warm blooded animal such as a person in need of therapeutic treatment And optionally a pharmaceutically acceptable diluent or carrier, comprising the following formulations:
[319] CETP (cholesteryl ester transfer protein) inhibitors, for example those referred to and described in WO 00/38725 (page 7, line 22 to page 17, line 17), incorporated herein by reference. ;
[320] Cholesterol absorption antagonists such as azetidinones, for example those described in SCH 58235 and US Pat. No. 5,767,115, which is incorporated herein by reference;
[321] MTP (microsomal transfer protein) inhibitors, for example those described in Science, 282, 751-54, 1998, incorporated herein by reference;
[322] Fibric acid derivatives such as clofibrate, gemfibrozil, fenofibrate, cipropibrate and benzfibrate;
[323] Nicotinic acid derivatives such as nicotinic acid (niacin), acipimox and niceritrol;
[324] Phytosterol compounds, for example stanol;
[325] Probucol;
[326] Anti-obesity compounds such as olistat (EP 129,748) and sibutramine (GB 2,184,122 and US Pat. No. 4,929,629);
[327] Antihypertensive compounds such as angiotensin converting enzyme inhibitors, angiothecin II receptor antagonists, adrenergic blockers, alpha adrenergic blockers, beta adrenergic blockers, mixed alpha / beta adrenergic blockers, adrenergic stimulants, calcium channel blockers, diuretics or blood vessels Extenders;
[328] Insulin;
[329] Sulfonylureas, including glybenclamide, tolbutamide;
[330] Metformin; And / or
[331] -Acarbos
[332] Combination therapies comprising the simultaneous, sequential or separate administration of one or more or pharmaceutically acceptable salts, solvates, solvates or prodrugs of such salts selected from among those provided.
[333] Certain ACE inhibitors, including active metabolites, or pharmaceutically acceptable salts, solvates, solvates or prodrugs of these salts, including active metabolites, which may be used in combination with a compound of formula (I), may be acelecfil, alatio Prills, Althiopryl Calcium, Ancobain, Benazepril, Benazepril Hydrochloride, Benazeprilat, Benzoylcaptopril, Captopril, Captopril-Cysteine, Captopril-Glutathione, Seranaphthyl, Serranopril, Serafnaph Phil, Silazapfil, Silazaprillat, Delapril, Delapril-Disan, Enalapril, Enalapril, Enapril, Epicaptopril, Poroxymytin, Phosenopril, Posenopril, Posenopril Sodium, Posinopril, Posinopril Sodium, Posinoprilat, Posinoprilate, Glycopyphil, Hemorphin-4, Idrapril, Imidapril, Indolapril, Indolaprilat, Ribenzapril, Risinopril, Risiu Min A, Rishiumin B, Myxanpril, Moexipril, Moexiprilat, Mobeltypril, Muracein A, Muracein B, Muracein C, Pentopril, Perindopril, Perindoprilat, Pivalopril , Fibopril, quinapril, quinapril hydrochloride, quinapril, ramipril, ramiprilat, spirapril, spirapril hydrochloride, spirapril, spiropril, spiropril hydrochloride, temocapryl, temocapryl hydrochloride, teprotid , But there are, but not limited to, trandolapril, trandolapril, utivapril, zabicipril, zabicprilat, zofenopril and zofenoprilat. Preferred ACE inhibitors for use in the present invention are ramipril, ramiprilat, ricinopril, enalapril and enalapril. More preferred ACE inhibitors for use in the present invention are ramipril and ramiprilat.
[334] Preferred angiotesin II antagonists, or pharmaceutically acceptable salts, solvates, solvates or prodrugs of these salts which can be used in combination with compounds of formula (I) include candesartan, candesartan cilexetil, Losartan, valsartan, ibesartan, tasosartan, telmisartan and eprosartan, but are not limited to these. Particularly preferred angiotesin II antagonists or pharmaceutically acceptable derivatives thereof for use in the present invention are candesartan and candesartan cilexetil.
[335] In another aspect of the invention, the compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, is a PPAR alpha and / or gamma agonist, or pharmaceutically acceptable Possible salts, solvates, solvates or prodrugs of such salts may be administered. Suitable PPAR alpha and / or gamma agonists, or pharmaceutically acceptable salts, solvates, solvates or prodrugs of these salts are well known in the art. These are WO 01/12187, WO 01/12612, WO 99/62870, WO 99/62872, WO 99/62871, 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 in J. Med. Chem., 2004, 43, 527. Including the compounds described, all of which are incorporated herein by reference, in particular the PPAR alpha / gamma agonists include WY-14643, clofibrate, fenofibrate, benzafibrate, GW 9578, troglitazone, pioglitazone, rosiglitazone , Egglitazone, proglitazone, BRL-49634, KRP-297, JTT-501, SB 213068, GW 1929, GW 7845, GW 0207, L-796449, L-165041 and GW 2433. PARR alpha and / or gamma agonists include (S) -2-ethoxy-3- [4- (2- {4-methanesulfonyloxyphenyl} ethoxy) phenyl] propionic acid and pharmaceutically acceptable salts thereof Means.
[336] Thus, in another aspect of the invention, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug PPAR thereof, of an effective amount is alpha in a warm blooded animal such as a person in need thereof. And / or simultaneous, sequential or separate administration with a gamma agonist, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, to produce an IBAT inhibitory effect in the animal. A method is provided.
[337] Thus, in another aspect of the invention, an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, of Treatment of hyperlipidemic conditions in said animal, comprising simultaneous, sequential or separate administration with a PPAR alpha and / or gamma agonist, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof A method is provided.
[338] According to another aspect of the invention, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, and a PPAR alpha and / or gamma agonist, or pharmaceutically thereof There is provided a pharmaceutical composition comprising an acceptable salt, solvate, solvate or prodrug of the salt in association with a pharmaceutically acceptable diluent or carrier.
[339] According to another aspect of the invention, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, and a PPAR alpha and / or gamma agonist, or pharmaceutically thereof Kits are provided that include acceptable salts, solvates, solvates or prodrugs of such salts.
[340] According to another aspect of the invention, there is provided a kit comprising the following (a) to (c):
[341] (a) a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, of the first unit dosage form;
[342] (b) PPAR alpha and / or gamma agonists, or pharmaceutically acceptable salts, solvates, solvates or prodrugs of the second unit dosage form; And
[343] (c) container means for containing said first unit dosage form and said second unit dosage form.
[344] According to another aspect of the invention, there is provided a kit comprising the following (a) to (c):
[345] (a) a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, of the first unit dosage form, and a pharmaceutically acceptable diluent or carrier;
[346] (b) PPAR alpha and / or gamma agonists, or pharmaceutically acceptable salts, solvates, solvates or prodrugs of the second unit dosage form; And
[347] (c) container means for containing said first unit dosage form and said second unit dosage form.
[348] According to another aspect of the invention, the compounds of formula (I), or pharmaceutically acceptable salts, solvates, solvates or pros thereof, in the preparation of a medicament for the production of an IBAT inhibitor effect in warm-blooded animals such as humans Drugs and PPAR alpha and / or gamma agonists, or pharmaceutically acceptable salts, solvates, solvates or prodrugs of such salts are provided.
[349] According to another aspect of the invention, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt, in the manufacture of a medicament for the treatment of hyperlipidemic conditions in warm-blooded animals such as humans, or Prodrugs and PPAR alpha and / or gamma agonists, or pharmaceutically acceptable salts, solvates, solvates or prodrugs of these salts are provided.
[350] According to another aspect of the invention, to a warm blooded animal such as a person in need of therapeutic treatment, an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable diluent or carrier, Solvates, solvates or prodrugs of such salts, optionally together with pharmaceutically acceptable diluents or carriers, and PPAR alpha and / or gamma agonists, or pharmaceutically acceptable salts, solvates, solvates of such salts Or combination therapy comprising administering simultaneously, sequentially or separately with the prodrug.
[351] In addition to use in therapeutic agents, the compounds of formula (I), or pharmaceutically acceptable salts, solvates, solvates or prodrugs thereof, are also cats, dogs, rabbits, monkeys as part of the study of novel therapeutic agents. It is also useful as a pharmacological tool in the development and standardization of in vitro and in vivo test systems for assessing the effects of inhibitors of IBAT in laboratory animals such as rats, mice.
[352] Many of the intermediates described herein are novel and therefore serve as further aspects of the present invention. For example, the compounds of formulas XIa, XIb, XIIa, XIIb, Xa and Xb exhibit IBAT inhibitory activity when tested in the in vitro test assays described above and are therefore claimed as another aspect of the invention.
[353] Thus, in another aspect of the present invention, there is provided a compound of formula (XIa), XIb, XIIa, XIIb, Xa and Xb, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof.
[354] Accordingly, according to another aspect of the present invention, a compound of formula (XIa), XIb, XIIa, XIIb, Xa and Xb, or a pharmaceutically acceptable salt, solvate, solvate or pro- ure thereof of the salts as defined above There is provided a pharmaceutical composition comprising a drug together with a pharmaceutically acceptable diluent or carrier.
[355] According to another aspect of the invention, a compound of formula (XIa), XIb, XIIa, XIIb, Xa and Xb, as defined above, for use in a method of prophylactic or therapeutic treatment of a warm blooded animal such as human Pharmaceutically acceptable salts, solvates, solvates or prodrugs of such salts are provided.
[356] Accordingly, according to this aspect of the invention, a compound of formula (XIa), XIb, XIIa, XIIb, Xa and Xb, or a pharmaceutically acceptable salt, solvate thereof, as defined above for use as a medicament Solvates or prodrugs of salts are provided.
[357] According to another aspect of the present invention, a compound of formula (XIa), XIb, XIIa, XIIb, Xa and Xb as defined above, or a pharmaceutical thereof, in the manufacture of a medicament for producing an IBAT inhibitory effect in a warm blooded animal such as a human Alternatively, acceptable salts, solvates, solvates or prodrugs of such salts are provided.
[358] According to another aspect of the invention, a compound of formula (XIa), XIb, XIIa, XIIb, Xa and Xb as defined above, or a pharmaceutical thereof, in the manufacture of a medicament for the treatment of hyperlipidemic conditions in warm-blooded animals such as humans Alternatively, acceptable salts, solvates, solvates or prodrugs of such salts are provided.
[359] According to another aspect of the invention, a compound of formula (XIa, XIb, XIIa, XIIb, Xa and Xb, or a pharmaceutically acceptable salt, solvate, solvent of said salts) in a warm blooded animal such as a person in need thereof A method is provided for producing an IBAT inhibitory effect in an animal comprising administering an effective amount of a cargo or prodrug.
[360] According to another aspect of the invention, a compound of formula (XIa, XIb, XIIa, XIIb, Xa and Xb, or a pharmaceutically acceptable salt, solvate, solvent of said salts) in a warm blooded animal such as a person in need thereof Provided is a method of treating a hyperlipidemic condition in an animal comprising administering an effective amount of a cargo or prodrug.
[361] In addition, in the other pharmaceutical compositions, methods, methods, uses and aspects of medicament manufacture, alternative and preferred embodiments of the compounds described herein apply,
[362] The present invention is now described in the following non-limiting examples, and standard techniques known to those skilled in the art and techniques similar to those described in these examples may be appropriately used in some cases, and unless otherwise stated, As follows:
[363] (i) evaporation is carried out by rotary evaporation under vacuum, and the post-treatment procedure is carried out by filtration to remove residual solids such as desiccants;
[364] (ii) all reactions were carried out using HPLC grade solvents under anhydrous conditions, at room temperature, typically in the range of 18-25 ° C., under inert atmosphere, unless otherwise noted;
[365] (iii) column chromatography (by flash procedure) was carried out on silica gel 40-63 μm (Merck);
[366] (iv) yields are given for illustrative purposes only and are not necessarily the maximum ones obtainable;
[367] (v) The structural formula of the final product of formula (I) was generally confirmed by nuclear (generally proton) magnetic resonance (NMR) and mass spectral techniques; Magnetic resonance chemical shift values (unless otherwise stated) were determined on a delta scale (ppm of downfield from tetramethylsilane) in deuterated CD ₃ OD; Proton data are quoted unless otherwise stated; Spectra were recorded on a Varian Mercury-300 MHz, Varian Unity plus-400 MHz, Varian Unity plus-600 MHz or Varian Inova-500 MHz spectrometers; s is the peak multiplicity of s (single), d (double), dd (double double), t (triple), tt (triple triple), q (triple), tq (triple triple), m (multiple), br Represented as (broad); LCMS was recorded on a Waters ZMD, LC column xTerra MS C ₈ (Waters) equipped with an HP 1100 MS-detector diode array; Mass spectra (MS) (loop) were recorded on the VG Platform II (Pigeon Instruments) equipped with an HP-100 MS-detector diode array; Unless stated otherwise, the cited mass ions were (MH ⁺ );
[368] (vi) Analytical high performance liquid chromatography (HPLC) was performed on Prep LC 2000 (Waters), Kromasil C ₈ , 7 μm (Azozo Nobel), unless details are specifically stated herein, MeCN and Ionic water 100 mM ammonia acetate was a mobile phase with a suitable composition;
[369] (vii) the intermediates were generally not sufficiently characterized and purity was assessed by thin layer chromatography (TLC), HPLC, IR, MS or NMR analysis;
[370] (viii) when drying the solution, the desiccant was sodium sulfate;
[371] (ix) when referring to an "ISOLUTE" column, this means a column containing 2 g of silica, said silicaka contained in a 6 ml disposable syringe, supported by a 54 Å pore sized porous disk, Purchased from International Sovent Technology as "ISOLUTE", "ISOLUTE" is a registered trade name;
[372] (x) The following abbreviations may be used as meanings defined before or after:
[373] DCM dichloromethane;
[374] DMFN, N-dimethylformamide;
[375] TFAtrifluoroacetic acid;
[376] TBTUo-benzotriazol-1-yl-N.N, N ', N'-tetraethyluronium tetrafluoroborate;
[377] EtOAc ethyl acetate; And
[378] MeCN acetonitrile.
[379] Example 1
[380] 1,1-dioxo-3 (R) -3-butyl-3-ethyl-5- (R) -5-phenyl-8- [N-((R) -α-carboxybenzyl)
[381] Carbamoylmethoxy] -2,3,4,5-tetrahydro-1,4-benzothiazepine; And
[382] 1,1-dioxo-3 (S) -3-butyl-3-ethyl-5- (S) -5-phenyl-8- [N-((R) -α-carboxybenzyl)
[383] Carbamoylmethoxy] -2,3,4,5-tetrahydro-1,4-benzothiazepine
[384] (+-)-Trans-1,1-dioxo-3-butyl-3-ethyl-5-phenyl-8- (carboxymethoxy) -2,3,4,5-tetrahydro-1,4-benzo Thiazine (method 1; 13 mg, 0.03 mmol) methyl (2R) -amino (phenyl) acetate (7.5 mg, 0.037 mmol) and diisopropylethylamine (24 mg, 0.19 mmol) are dissolved in DCM (1.5 ml) I was. The mixture was stirred for 10 minutes, then TBTU (12 mg, 0.037 mmol) was added and the reaction mixture was stirred for 30 minutes. The solvent was removed under reduced pressure. The residue was dissolved in ethanol (2 ml) and sodium hydroxide (2 mg) was added. The mixture was stirred for 30 minutes and then the solvent was evaporated. The residue was purified by chromatography (DCM: EtOAc: AcOH, 100: 10: 3) to give the title compound (5.5 mg, 32%). M / z: 565.3 (MH < + >), 563.2 (M−).
[385] Example 2
[386] 1, l-Dioxo-3 (R) -3-butyl-3-ethyl-5- (R) -5-phenyl-8- (N-{(R) -α- [N- (carboxymethyl) carr Barmoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,4-benzothiazepine; And 1,1-dioxo-3 (S) -3-butyl-3-ethyl-5- (S) -5-phenyl-8- (N-{(R) -α- [N- (carboxymethyl) Carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,4-benzothiazepine
[387] 1,1-dioxo-3- (R) -3-butyl-3-ethyl-5- (R) -5-phenyl-8- (N-{(R) -α- [N- (t-part Methoxycarbonylmethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,4-benzothiazepine and 1,1-dioxo-3- (S)- 3-butyl-3-ethyl-5- (S) -5-phenyl-8- (N-{(R) -α- [N- (t-butoxycarbonylmethyl) carbamoyl] benzyl} carba An isomixture of molemethoxy) -2,3,4,5-tetrahydro-1,4-benzothiazepine (method 2; 27 mg, 0.040 mmol) was dissolved in 2 ml of DCM. Trifluoroacetic acid (0.2 ml, 2.60 mmol) was added and the mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated under reduced pressure and then purified by preparative HPLC using MeCN / ammonium acetate buffer gradient (5/95 to 60/40) as eluent. MeCN was evaporated and the remaining solution was lyophilized to give the title product in 69% yield (16 mg). NMR (400 MHz, MeOD): 0.81 (t, 3H), 0.89 (t, 3H), 1.11-1.35 (m, 4H), 1.41-1.50 (m, 1H), 1.52-1.62 (m, 1H), 1.74 -1.84 (m, 1H), 2.17-2.28 (m, 1H), 3.34 (ABq, 2H), 3.87 (ABq, 2H), 4.63-4.66 (m, 2H), 5.61 (s, 1H), 6.00 (s , 1H), 6.59-6.64 (m, 1H), 6.95-7.01 (m, 1H), 7.27-7.44 (m, 10H), 7.64-7.67 (m, 1H); m / z: 622 (M + 1) .
[388] Example 3
[389] 3,5-trans-1,1-dioxo-3-ethyl-3-butyl-5-phenyl-7-bromo-8- (N-{(R) -α- [N- (carboxymethyl) car Barmoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,4-benzothiazepine
[390] 3,5-trans-1,1-dioxo-3-ethyl-3-butyl-5-phenyl-7-bromo-8- (carboxymethoxy) -2,3,4,5-tetrahydro-1 , 4-benzothiazepine (method 5; 50 mg, 0.10 mmol) was dissolved in DCM (3 ml). Rutidine (0.023 ml, 0.198 mmol), TBTU (38 mg, 0.118 mmol) and (R) -α- [N- (t-butoxycarbonylmethyl) carbamoyl] benzylamine (method 4; 44 mg, 0.167 mmol) was added continuously. The mixture was stirred at ambient temperature overnight. The solution was concentrated to 1 ml and TFA (1.3 ml) was added. The mixture was concentrated after 1.5 h and the residue was purified using preparative HPLC. As eluent a gradient of 40% to 60% MeCN in 0.1 M ammonium acetate was used. Lyophilization gave a yield of 39 mg (57%). NMR (400 MHz) 0.75 (t, 3H), 0.95 (t, 3H), 1.2-1.4 (m, 6H), 1.75-1.9 (m, 1H), 2.2-2.4 (m, 1H), 3.35 (dd, 2H), 3.85 (dd, 2H), 4.7-4.8 (m, 2H), 5.6 (s, 1H), 6.0 (d, 1H), 6.8 (d, 1H), 7.25- 7.5 (m, 10H), 7.6 (d, 1H); m / z: 700 (M) and 702 (M + 2) ²⁺ .
[391] Example 4
[392] 3,5-trans-1,1-dioxo-3- (S) -3-ethyl-3-butyl-4-hydroxy-5- (S) -5-phenyl-7-bromo-8- ( N-{(R) -α- [N- (carboxymethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,4-benzothiazepine
[393] 3.5-trans-1,1-dioxo-3- (R) -3-ethyl-3-butyl-4-hydroxy-5- (R) -5-phenyl-7-bromo-8- (N- {(R) -α- [N- (carboxymethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,4-benzothiazepine
[394] 3,5-trans-1,1-dioxo-3-ethyl-3-butyl-5-phenyl-7-bromo-8- (N- (R) -α- [N- (carboxymethyl) carba Moyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,4-benzothiazepine (Example 3; 14 mg, 0.02 mmol) was dissolved in 2 ml of DCM. m-chloroperoxybenzoic acid (5.5 mg, 0.022 mmol) was added and the mixture was stirred for 30 minutes. Preparation on C8 Column The diastereomer of the title compound was isolated using HPLC. As eluent a gradient of MeCN of 30% to 60% in 0.1 M ammonium acetate buffer was used. Both compounds were lyophilized and the first eluting diastereomer was 5.4 mg and the second was 4.9 mg. M / z: 716 (M) and 718 (M + 2) ²⁺ . NMR (400 MHz) (Diesteromer 1) 0.86 (t, 3H), 0.95 (t, 3H), 1.1-1.4 (m, 3H), 1.4-1.55 (m, 2H), 1.68-1.8 (m, 1H ), 2.0-2.2 (m, 2H), 3.4 (dd, 2H), 3.88 (Abq, 2H), 4.76 (Abq, 2H), 5.6 (s, 1H), 6.45 (s, 1H), 6. 88 ( s, 1 H), 7.25-7.50 (m, 10 H), 7.56 (s, 1 H). NMR (Diestereoster 2) (400 MHz) 0.87 (t, 3H), 0.95 (t, 3H), 1.1-1.4 (m, 3H), 1.4-1.55 (m, 2H), 1.68-1.8 (m, 1H ), 2.0-2.22 (m, 2H), 3.4 (dd, 2H), 3.82 (Abq, 2H), 4.76 (Abq, 2H), 5.6 (s, 1H), 6.46 (s, 1H), 6.88 (s, 1H), 7.25-7.50 (m, 10H), 7.57 (s, 1H).
[395] Example 5
[396] 3,5-trans-1,1-dioxo-3-ethyl-3-butyl-5-phenyl-7-methylthio-8- (N- (R) -α- [N- (carboxymethyl) carba Moyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,4-benzothiazepine
[397] 3,5-trans-1,1-dioxo-3-ethyl-3-butyl-5-phenyl-7-methylthio-8- (carboxymethoxy) -2,3,4,5-tetrahydro-1 , 4-benzothiazepine (method 6; 50 mg, 0.105 mmol) was dissolved in DCM (2 ml). 2,6-lutidine (0.025 ml, 0.215 mmol), TBTU (45 mg, 0.140 mmol) and (R) -α- [N- (t-butoxycarbonylmethyl) carbamoyl] benzylamine (method 4 43 mg, 0.163 mmol) was added continuously. The mixture was stirred at ambient temperature for 2 hours. The solution was concentrated and the intermediate ester was purified by chromatography on silica gel using DCM / EtOAc (9/1) as eluent. The solvent was evaporated to yield 45 mg (60%). M / z: 724. The ester was dissolved in 3 ml DCM and hydrolyzed by the addition of TFA (1 ml). After 2 h the mixture was concentrated and purified using preparative HPLC. As eluent an gradient of MeCN of 40% to 60% in 0.1 M ammonium acetate buffer was used. Lyophilization yield was 33 mg (80%). NMR (400 MHz): 0.75-0.85 (m, 3H), 0.85-0.95 (m, 3H), 1.1-1.65 (m, 6H), 1.75-1.9 (m, 1H), 2.0 (s, 3H), 2.2 -2.4 (m, 1H), 3.1-3.55 (m, 2H), 3.85 (ABq, 2H), 4.6-4.8 (m, 2H), 5.6 (s, 1H), 5.98-6.03 (m, 1H), 6.4 (s, 1 H), 7.25-7.56 (m, 11 H); m / z: 668.
[398] Example 6
[399] 3,5-trans-1,1-dioxo-3-ethyl-3-butyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N- (2-sulfoethyl ) Carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,4-benzothiazepine ammonia salt
[400] 3,5-trans-1,1-dioxo-3-ethyl-3-butyl-5-phenyl-7-methylthio-8- (carboxymethoxy) -2,3,4,5-tetrahydro-1 , 4-benzothiazepine (method 6; 33 mg, 0.070 mmol) was dissolved in DMF (3 ml). 2-{[(2R) -2-amino-2- (4-hydroxyphenyl) ethanoyl] amino} ethanesulfonic acid (method 8; 23 mg, 0.084 mmol), N-methylmorpholine (0.025 ml, 0.227 mmol) and TBTU (27 mg, 0.084 mmol) were added sequentially and the mixture was stirred overnight. Solvent was removed and crude product was purified using preparative HPLC. As eluent a gradient of MeCN of 40% to 70% in 0.1 M ammonium acetate buffer was used. Lyophilization gave 42 mg (80%) of ammonium salt. NMR (400 MHz): 0.73-0.85 (m, 3H), 0.85-0.98 (m, 3H), 1.1-1.7 (m, 6H), 1.75-1.9 (m, 1H), 2.0 (s, 3H), 2.15 -2.4 (m, 1H), 2.85-3.0 (m, 2H), 3.1-3.55 (m, 2H), 3.5-3.65 (m, 2H), 4.6-4.8 (m, 2H), 5.35-5.39 (m, 1H), 5.98-6.05 (m, 1H), 6.4 (s, 1H), 6.75 (d, 2H), 7.15-7.5 (m, 8H); m / z: 734.
[401] Example 7
[402] 1,1-dioxo-3- (S) -3-ethyl-3-butyl-5- (S) -5-phenyl-7-methylthio-8- (N-{(R) -α- [N (Carboxymethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3.4,5-tetrahydro-1.4-benzothiazepine diethylamine salt
[403] 1,1-dioxo-3- (R) -3-ethyl-3-butyl-5- (R) -5-phenyl-7-methylthio-8- (N-{(R) -α- [N -(Carboxymethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,4-benzothiazepine diethylamine salt
[404] 3,5-trans-1,1-dioxo-3-ethyl-3-butyl-5-phenyl-7-methylthio-8- (N-{(R) by chiral chromatography on a Chirobiotic V chiral stationary phase -α- [N- (carboxymethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,4-benzothiazepine (Example 5; 17 mg, 0.026 mmol) was separated. A series of two columns (250 x 20 mm) was used. A fluidized bed consisting of 0.1% Et ₃ N and 0.1% HOAc and 80% MeOH in water was used as eluent. The first eluting diastereomer was collected into 50 ml of fraction and the solvent was removed under reduced pressure. Nt analysis showed that Et ₃ N remained and the diastereomer was purified by chromatography on 0.5 g Si0 ₂ using DCM / MeOH (9/1) as eluent. The solvent was removed and the product dissolved in water and some MeCN. Lyophilization gave a white solid, which was dissolved in MeOH and filtered. Secondly, lyophilization gave diastereomer as 1 mg (4%) of Et ₃ N salt. M / z: 668. In Example 5 NMR (HOAc-d 4) was constant. ee was measured at 99%. A second eluting diastereomer was collected in 200 ml of the fraction and the solvent was removed under reduced pressure. The residue was purified using preparative HPLC on C8 column. A 35% to 50% MeCN gradient in 0.1 M ammonium acetate was used as eluent. Lyophilization gave the diastereomer as 3 mg (17 mg) of Et ₃ N salt. M / z: 668. ee was measured at 97%.
[405] Preparation of Starting Material
[406] Starting materials for these examples are readily prepared by standard methods from commercially known or known materials. For example, the following reactions are illustrative of, but not limited to, some of the starting materials used in the reactions.
[407] Method 1
[408] (+-)-Trans-1,1-dioxo-3-butyl-3-ethyl-5-phenyl-8- (carboxymethoxy) -2,3,4,5-tetrahydro-1,4-benzo Tiazine
[409] 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-8-hydroxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (according to WO / 9605188) 83 mg, 0,22 mmol), ethyl bromoacetate (55 mg, 0.33 mmol) and sodium carbonate (70 mg, 0.66 mmol) in acetonitrile (3 ml) were warmed to reflux for 40 hours. The solvent was removed under reduced pressure and the crude product was dissolved in ethanol (4 ml). Sodium hydroxide (0.1 g) was added and the mixture was warmed to reflux for 1 hour. The solvent was removed under reduced pressure and the residue was partitioned between DCM and 2 M acetic acid. The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by chromatography (EtOAc: formic acid, 500: 1) to give 61 mg (64%) of the title compound. NMR (500 MHz, CDCl ₃ ): 0.86 (t, 3H), 0.92 (t, 3H), 1.0-1.05 (m, 1H), 1.2-1.4 (m, 3H), 1.6-1.75 (m, 2H), 1.85-1.95 (m, 1H), 2.38-2.47 (m, 1H), 3.45 (s, 2H), 4.5 (s, 2H), 6.17 (s, 1H), 6.75 (d, 1H), 6.86 (dd, 1H), 7.37-7. 5 (m, 5H), 7.64 (d, 1H).
[410] Method 2
[411] 1,1-dioxo-3 (R) -3-butyl-3-ethyl-5- (R) -5-phenyl-8- (N-{(R) -α- [N- (t-butoxy Carbonylmethyl) carbamoylbenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,4-benzothiazepine: and 1,1-dioxo-3 (S) -3- Butyl-3-ethyl-5- (S) -5-phenyl-8- (N-{(R) -α- [N- (t-butoxycarbonylmethyl) carbamoylbenzyl} carbamoylmethoxy ) -2,3,4,5-tetrahydro-1,4-benzothiazepine
[412] (+-)-Trans-1,1-dioxo-3-butyl-3-ethyl-5-phenyl-8- (carboxymethoxy) -2,3,4,5-tetrahydro-1,4-benzo Thiapine (method 1; 17.5 mg, 0.041 mmol) was dissolved in DCM (3 ml). 2,6-lutidine (0.010 ml, 0.086 mmol), TBTU (16.4 mg, 0.051 mmol) and (R) -α- [N- (t-butoxycarbonylmethyl) carbamoyl] benzylamine (method 4 16.3 mg, 0.062 mmol) was added continuously. The mixture was stirred at ambient temperature for 1 hour. The solution was concentrated and the crude product was purified by chromatography on silica gel using DCM / EtOAc (8/2) as eluent. The solvent was evaporated and the title product was obtained in 98% yield (27 mg). M / z: 678 (M + l).
[413] Method 3
[414] (R) -N-benzyloxycarbonyl-α- [N- (t-butoxycarbonylmethyl) carbamoyl] benzylamine
[415] (2R)-{[(benzyloxy) carbonyl] amino} (phenyl) acetic acid (10 g, 35.0 mmol) and t-butylglycine hydrochloride (6.3 g, 37.4 mmol) were added to 2,6-lutidine (8.2 ml). , 70.4 mmol) in DCM (200 ml). Stirred at 0 ° C. for 5 minutes, then TBTU (12.4 g, 38. 6 mmol) was added and stirring continued at 0 ° C. for 1.5 hours and at room temperature for 3.75 hours. The reaction mixture was washed with water (2 x 100 ml), dried (MgSO ₄ ) and purified by flash chromatography (DCM: EtOAc 7: 1-> 5: 1) to afford the title compound (13 g, 94%). . NMR (500 MHz, CDC13): 1.45 (s, 9H), 3.84 (d, 1H), 4.00 (dd, 1H), 5.10 (m, 2H), 5.28 (brs, 1H), 6.13 (brs, 1H), 6.23 (brs, 1 H), 7.30-7.44 (m, 10H).
[416] Method 4
[417] (R) -α- [N- (t-butoxycarbonylmethyl) carbamoyl] benzylamine
[418] (R) -N-benzyloxycarbonyl-α- [N- (t-butoxycarbonylmethyl) carbamoyl] benzylamine (method 3; 12.8 g, 32.2 mmol) was added to EtOH (99%, 200 ml). And toluene (50 ml). Pd / C (10%, 0.65 g) was added and hydrogenated at room temperature for 5.5 hours at atmospheric pressure. The reaction mixture was filtered through diatomaceous earth and the solvent was evaporated to give the title compound (8.4 g, 99%). NMR (600 MHz, CDCl ₃ ): 1.45 (s, 9H), 3.93 (m, 2H), 4.54 (s, 1H), 7.31-7.42 (m, SH), 7.51 (brs, 1H).
[419] Method 5
[420] 3,5-trans-1,1-dioxo-3-ethyl-3-butyl-5-phenyl-7-bromo-8- (carboxymethoxy) -2,3,4,5-tetrahydro-1 , 4-benzothiazepine
[421] (+/-)-trans-7-bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-ol, 1, The title compound was prepared as described in Method 6 starting from 1-dioxide (W096 / 05188; 81 mg, 0.18 mmol.) The intermediate ethyl ester was obtained in 94% yield (m / z: 538 (M)). And 540 (M + 2)) The product was obtained at 50 mg (58%) NMR 0.75 (t, 3H), 0.95 (t, 3H), 1.2-1.45 (m, 6H), 1.75-1.9 (m, 1H), 2.2-2.4 (m, 1H), 3.35 (dd, 2H), 4.8 (s, 2H), 6.0 (s, 1H), 6.8 (s, 1H), 7.3-7.5 (m, 5H), 7.55 (s, 1 H); m / z: 510 (M) and 512 (M + 2) ²⁺ .
[422] Method 6
[423] 3,5-trans-1,1-dioxo-3-ethyl-3-butyl-5-phenyl-7-methylthio-8- (carboxymethoxy) -2,3,4,5-tetrahydro-1 , 4-benzothiazepine
[424] 3,5-trans-1, l-dioxo-3-ethyl-3-butyl-5-phenyl-7-methylthio-8-hydroxy-2,3,4,5 using the procedure described in Method 1 The title compound was prepared from tetrahydro-1,4-benzothiazepine (method 7; 153 mg, 0.36 mmol). The intermediate ethyl ester was extracted between diluted HC1 and DCM. The DCM phase was washed with brine, dried over Na ₂ SO ₄ and concentrated. M / z 506. The crude product was dissolved in THF / H ₂ O (3/1; 4 ml) and LiOH (22 mg, 0.91 mmol) was added. The mixture was stirred for 2 hours and the solvent was removed under reduced pressure. The crude product was purified using preparative HPLC. As eluent 40% to 60% MeCN gradient in 0.1 M ammonium acetate buffer was used. MeCN was removed under reduced pressure and the remaining aqueous solution was acidified with 5% HCl and extracted with DCM. The DCM layer was dried over Na ₂ S0 ₄ and concentrated. The crude product was co-evaporated with diethyl ether. The obtained crystals were filtered and dried. Mass: 158 mg (91%). NMR 0.75 (t, 3H), 0.9 (t, 3H), 1.1-1.7 (m, 6H), 1.7-1.9 (m, 1H), 2.0 (s, 3H), 2.2-2.4 (m, lH), 3.3 (dd, 2H), 4.75 (s, 2H), 6.0 (s, 1H), 6.4 (s, 1H), 7.3-7.5 (m, 6H); m / z: 478.
[425] Method 7
[426] 3,5-trans-1,1-dioxo-3-ethyl-3-butyl-5-phenyl-7-methylthio-8-hydroxy-2,3,4,5-tetrahydro-1,4- Benzothiazepine
[427] (+/-)-trans-7-bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine 1, 1-dioxide (prepared according to WO 96/05188; 300 mg, 0.64 mmol) was dissolved in 5 ml of DMF under N ₂ (g) -atmosphere. Sodium thiomethylate (150 mg, 2.14 mmol) was added and the mixture was heated to 110 ° C. for 2 hours. The solvent was removed under reduced pressure and the residue extracted between 5% HC1 and EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. Preparation The product was purified using HPLC. A 40% to 100% MeCN gradient in 0.1 M ammonium acetate buffer was used as eluent. 153 mg, 57% was obtained by freeze drying. M / z: 420.
[428] Method 8
[429] 2-{[(2R-2-amino-2- (4-hydroxyphenyl) ethanoyl] amino} ethanesulfonic acid
[430] N-Boc- (D) -4-hydroxyphenylglycine (1.00 g, 3.21 mmol) was dissolved in DMF (5 ml) and tetrabutylammonium taurine (2.36 g, 6.42 mmol) was added with additional DMF (5 ml). Added together. The resulting suspension was cooled on ice and TBTU (1.24 g, 3.85 mmol) was added. After 30 minutes the ice bath was removed and the mixture was stirred for 2 hours, then filtered and concentrated. TFA (20%, 20 ml) in DCM was added and the reaction mixture was stirred overnight. Ethanol (20 ml) was added and the solvent was evaporated. The crude product was refluxed in ethanol (100 ml) for 1 hour. Filtration gave the pure title compound as 626 mg (71%) of a white solid. NMR (DMSO-d ₆ ): 2.4-2.6 (m, 2H), 3.2-3.4 (m, 2H), 4.79 (s, 1H), 6.78 (d, 2H), 7.23 (d, 2H), 8.22 (t , 1H), 8.4 (brs, 3H), 9.7 (s, 1H).

权利要求:
Claims (23)
[1" claim-type="Currently amended] A compound of formula (I) or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof.
Formula I

[In the above formula, one of R ¹ and R ² is selected from hydrogen, C _1-6 alkyl or C _2-6 alkenyl, the other is selected from C _1-6 alkyl or C _2-6 alkenyl;
R ^y is selected from hydrogen, hydroxy, C _1-6 alkyl, C _1-4 alkoxy and C _1-6 alkanoyloxy;
R ^z is halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1- 6} alkoxy, C _1-6 alkanoyl, C _1-6 alkanoyloxy, N- (C _1-6 alkyl) amino, N, N- (C _1-6 alkyl) ₂ amino, C _1-6 alkanoylamino , N- (C _1-6 alkyl) carbamoyl, N, N- (C _1-6 alkyl) ₂ carbamoyl, C _1-6 alkylS (O) _a (where a is 0 to 2), C _1-6 alkoxycarbonyl, N- (C _1-6 alkyl) sulfamoyl and N, N- (C _1-6 alkyl) ₂ sulfamoyl;
v is 0-5;
One of R ⁴ and R ⁵ is a group of formula ( IA )
The other of R ³ and R ⁶ and R ⁴ and R ⁵ is independently hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _1-4 alkanoyl, C _1-4 alkanoyloxy, N- (C _1-4 alkyl) amino, N, N- ( C _1-4 alkyl) ₂ amino, C _1-4 alkanoylamino, N- (C _1-4 alkyl) carbamoyl, N, N- (C _1-4 alkyl) ₂ carbamoyl, C _1-4 Alkyl S (O) _a (where a is 0-2), C _1-4 alkoxycarbonyl, N- (C _1-4 alkyl) sulfamoyl and N, N- (C _1-4 alkyl) ₂ sulfamoyl Wherein the other of R ³ and R ⁶ and R ⁴ and R ⁵ may be optionally substituted on carbon with one or more R ¹⁶ ;
Formula IA

Wherein X is -O-, -N (R ^a )-, -S (O) _b -or -CH (R ^a ), where R ^a is hydrogen or C _1-6 alkyl and b is 0-2 );
Ring A is aryl or heteroaryl, which is optionally substituted with one or more substituents selected from R ¹⁷ ;
R ⁷ is hydrogen, C _1-4 alkyl, carbocyclic or heterocyclic, which is optionally substituted by one or more substituents selected from R ¹⁸ ;
R ⁸ is hydrogen or C _1-4 alkyl;
R ⁹ is hydrogen or C _1-4 alkyl;
R ¹⁰ is hydrogen, C _1-4 alkyl, carbocyclic or heterocyclic, which is optionally substituted by one or more substituents selected from R ¹⁹ ;
R ¹¹ is carboxy, sulfo, sulfino, phosphono, -P (O) (OR ^c ) (OR ^d ), -P (O) (OH) (OR ^c ), -P (O) (OH) (R ^d ) or —P (O) (OR ^c ) (R ^d ) wherein R ^c and R ^d are independently selected from C _1-6 alkyl, or R ¹¹ is a group of formula IB
Formula IB

Where Y is -N (R ^x )-, -N (R ^x ) C (O)-, -O-, and -S (O) a-, where a is 0-2 and R ^x is hydrogen or C _1-4 alkyl);
R ¹² is hydrogen or C _1-4 alkyl;
R ¹³ and R ¹⁴ are independently selected from hydrogen, C _1-6 alkyl, carbocyclic or heterocycle, and R ¹³ and R ¹⁴ may be independently substituted by one or more substituents selected from R ²⁰ ;
R ¹⁵ is carboxy, sulfo, sulfino, phosphono, -P (O) (OR ^e ) (OR ^f ), -P (O) (OH) (OR ^e ), -P (O) (OH) (R ^e) or ^{-P (O) (oR e)} (R f) ( wherein, R ^e and R ^f are independently selected from C _1-6 alkyl) or R ¹⁵ is a group of the formula IC to inde,
Chemical Formula IC

Wherein R ²⁴ is selected from hydrogen or C _1-4 alkyl;
R ²⁵ is selected from hydrogen, C _1-4 alkyl, carbocyclic, heterocyclic or R ²⁷ , wherein C _1-4 alkyl, carbocyclic or heterocyclic is independently substituted by one or more substituents selected from R ²⁸ . Could be;
R ²⁶ is carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P (O) (OR ^g ) (OR ^h ), -P (O) (OH) (OR ^g ), -P (O) (OH ) (R ^g ) or -P (O) (OR ^g ) (R ^h ), wherein R ^g and R ^h are independently selected from C _1-6 alkyl:
p is 1-3 (wherein the groups of R ¹³ may be the same or different);
q is 0 to 1;
r is 0-3, where the groups of R ¹⁴ may be the same or different;
m is 0-2 where the groups of R ¹⁰ may be the same or different;
n is 1-3 (wherein groups of R ⁷ may be the same or different);
z is 0-3, where the groups of R ²⁵ may be the same or different;
R ¹⁶ , R ¹⁷ and R ¹⁸ are independently halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-4 alkyl, C _2-4 alkenyl, C _{2 -4} alkynyl, C _1-4 alkoxy, C _1-4 alkanoyl, C _1-4 alkanoyloxy, N- (C _1-4 alkyl) amino, N, N- (C _1-4 alkyl) ₂ amino , C _1-4 alkanoylamino, N- (C _1-4 alkyl) carbamoyl, N, N- (C _1-4 alkyl) ₂ carbamoyl, C _1-4 alkylS (O) _a (where a is 0-2), C _1-4 alkoxycarbonyl, N- (C _1-4 alkyl) sulfamoyl and N, N- (C _1-4 alkyl) ₂ sulfamoyl, wherein R ¹⁶ , R ¹⁷ and R ¹⁸ may independently be optionally substituted on carbon by one or more R ²¹ ;
R ¹⁹ ,R ²⁰ ,R ²⁷ AndR ²⁸ Are independently halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C_1-4Alkyl, C_2-4Alkenyl, C_2-4Alkynyl, C_1-4Alkoxy, C_1-4Alkanoyl, C_1-4Alkanoyloxy, N- (C_1-4Alkyl) amino, N, N- (C_1-4Alkyl)₂Amino, C_1-4Alkanoylamino, N- (C_1-4Alkyl) carbamoyl, N, N- (C_1-4Alkyl)₂Carbamoyl, C_1-4Alkyl S (O)_a(Where a is 0 to 2), C_1-4Alkoxycarbonyl, N- (C_1-4Alkyl) sulfamoyl, N, N- (C_1-4Alkyl)₂Sulfamoyl, carbocyclic, heterocyclic, sulfo, sulfino, amidino, (C_1-4Alkyl)₃Silyl, 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^aAnd R^bIs independently C_1-6Selected from alkyl) and R¹⁹And R²⁰Is independently 1 or more R²²May be optionally substituted on carbon by;
R ²¹ and R ²² are independently halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl , Ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N , N-dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl and N, N-dimethylsulfamoyl.] [2" claim-type="Currently amended] The compound of formula I or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, according to claim 1, wherein one of R ¹ and R ² is ethyl and the other is butyl.
[3" claim-type="Currently amended] The compound of formula (I) or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, according to claim 1 or 2, wherein R ^y is hydrogen or hydroxy.
[4" claim-type="Currently amended] The compound of formula (I) or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, according to any one of claims 1 to 3, wherein v is zero.
[5" claim-type="Currently amended] The compound of formula (I) or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, according to any one of claims 1 to 4, wherein R ³ and R ⁶ are hydrogen.
[6" claim-type="Currently amended] 6. The compound of formula I or a pharmaceutical thereof according to claim 1, wherein R ⁴ is hydrogen, halo or C _1-4 alkylS (O) _a , wherein a is 0. 7. Acceptable salts, solvates, solvates or prodrugs of such salts.
[7" claim-type="Currently amended] The compound of any one of claims 1 to 6, wherein R ⁵ is a group of formula IA (as shown above), wherein
X is -O-;
Ring A is phenyl or 4-hydroxyphenyl;
R ⁷ is hydrogen;
R ⁸ is hydrogen;
R ⁹ is hydrogen;
R ¹¹ is carboxy or a group of formula IB (as shown above), wherein
R ¹² is hydrogen;
R ¹³ is hydrogen;
R ¹⁵ is carboxy or sulfo;
p is 1 or 2;
q is 0;
r is 0;
m is 0;
n is 1
A compound of formula (I) or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof.
[8" claim-type="Currently amended] R ¹ and R ² are C _1-4 alkyl;
v is 0;
R ^y is hydrogen or hydroxy;
R ³ and R ⁶ are hydrogen,
R ⁴ is hydrogen, halo or C _1-4 alkylS (O) _a , where a is 0;
R ⁵ is a group of formula IA (as shown above) wherein
X is -O-;
Ring A is aryl (ring A is optionally substituted with one or more substituents selected from R ¹⁷ );
R ⁷ is hydrogen;
R ⁸ is hydrogen;
R ⁹ is hydrogen;
R ¹¹ is carboxy or a group of formula IB (as shown above) wherein:
R ¹² is hydrogen;
R ¹³ is hydrogen;
R ¹⁵ is carboxy or sulfo;
p is 1 or 2;
q is 0;
r is 0;
m is 0;
n is 1;
R ¹⁷ is hydroxy
A compound of formula I (as shown above) or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof.
[9" claim-type="Currently amended] 1,1-dioxo-3 (R) -3-butyl-3-ethyl-5- (R) -5-phenyl-8- [N-((R) -α-carboxybenzyl) carbamoylmethoxy ] -2,3,4,5-tetrahydro-1,4-benzothiazepine;
1,1-dioxo-3 (S) -3-butyl-3-ethyl-5- (S) -5-phenyl-8- [N-((R) -α-carboxybenzyl) carbamoylmethoxy ] -2,3,4,5-tetrahydro-1,4-benzothiazepine;
1,1-dioxo-3 (R) -3-butyl-3-ethyl-5- (R) -5-phenyl-8- (N-{(R) -α- [N- (carboxymethyl) carr Barmoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,4-benzothiazepine;
1,1-dioxo-3 (S) -3-butyl-3-ethyl-5- (S) -5-phenyl-8- (N-{(R) -α- [N- (carboxymethyl) carr Barmoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,4-benzothiazepine;
3,5-trans-1,1-dioxo-3-ethyl-3-butyl-5-phenyl-7-bromo-8- (N-{(R) -α- [N- (carboxymethyl) car Barmoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,4-benzothiazepine;
3,5-trans-1,1-dioxo-3- (S) -3-ethyl-3-butyl-4-hydroxy-5- (S) -5-phenyl-7-bromo-8- ( N-{(R) -α- [N- (carboxymethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,4-benzothiazepine;
3,5-trans-1,1-dioxo-3- (R) -3-ethyl-3-butyl-4-hydroxy-5- (R) -5-phenyl-7-bromo-8- ( N-{(R) -α- [N- (carboxymethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,4-benzothiazepine;
3,5-trans-1,1-dioxo-3-ethyl-3-butyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N- (carboxymethyl) car Barmoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,4-benzothiazepine;
3,5-trans-1,1-dioxo-3-ethyl-3-butyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N- (2-sulfoethyl ) Carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,4-benzothiazepine ammonia salt
1,1-dioxo-3 (S) -3-ethyl-3-butyl-5- (S) -5-phenyl-7-methylthio-8- [N-{(R) -α- [N- Carboxymethyl) carbamoyl] benzyl} carbamoylmethoxy] -2,3,4,5-tetrahydro-1,4-benzothiazepine diethylamine salt; And
1,1-dioxo-3 (R) -3-ethyl-3-butyl-5- (R) -5-phenyl-7-methylthio-8- (N-{(R) -α- [N- (Carboxymethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,4-benzothiazepine diethylamine salt;
A compound of formula (I) selected from pharmaceutically acceptable salts, solvates, solvates or prodrugs of such salts.
[10" claim-type="Currently amended] A method of preparing a compound of formula (I) or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof of any one of claims 1 to 9, wherein any one of the following methods 1) to 10): A process comprising the following processes and, if necessary or preferred, the following i) to iii):
Method 1) A method of oxidizing benzothiazepine of formula II:
Formula II

Method 2) For compounds of formula I, wherein X is -O-, -NR ^a or -S-, the method of reacting a compound of formula IIIa or IIIb with a compound of formula IV:
Formula IIIa

Formula IIIb

Formula IV

In the above formula, L is a substitutable group
Method 3): A method of reacting an acid of formula Va or Vb or an active derivative thereof with an amine of formula VI:
Chemical formula Va

Formula Vb

Formula VI

Method 4): For compounds of formula (I), in which R ¹¹ is a group of formula (IB), a method of reacting a compound of formula (I) wherein R ¹¹ is carboxyl with an amine
Formula VII

Method 5) For compounds of formula I, wherein R ¹¹ is a group of formula IB and R ¹⁵ is a group of formula IC, the compound of formula I wherein R ¹⁵ is carboxyl is reacted with an amine of formula VIII:
Formula VIII

Method 6): For compounds of formula I wherein one of R ⁴ and R ⁵ is independently selected from C _1-6 alkylthio optionally substituted with one or more R ¹⁶ on carbon, the compound of formula IXa or IXb is Reaction with thiol of X:
Formula IXa

Formula IXb

Formula X
R ^m -H
In the formulas above, L is a substitutable group and R ^m is C _1-6 alkylthio optionally substituted with one or more R ¹⁶ on carbon.
Method 7) For compounds of formula I, wherein R ¹¹ is carboxy, the method for deprotecting a compound of formula XIa or XIb:
Formula XIa

Formula XIb

In the above formulas, R ^x forms an ester with the —OC (O) — group to which it is attached
Method 8): For compounds of formula I, wherein R ¹¹ is a group of formula IB and R ¹⁵ is carboxy, the method for deprotecting a compound of formula XIIa or XIIb:
Formula XIIa

Formula XIIb

In the above formula, R ^x forms an ester with the —OC (O) — group to which it is attached
Method 9): For compounds of formula I, wherein R ¹¹ is a group of formula IB and Y is -N (R ^x ) C (O)-, an acid of formula XIIIa or XIIIb or an active derivative thereof Reaction with amines:
Formula XIIIa

Formula XIIIb

Formula XIV

Or method 10) for compounds of formula I, wherein R ¹¹ is a group of formula IB, R ¹⁵ is a group of formula IC, and R ²⁶ is carboxy, a method for deprotecting a compound of formula XVa or XVb:
Formula XVa

Formula XVb

In the above formula, R ^x forms an ester with the —OC (O) — group to which it is attached
i) converting a compound of formula (I) to another compound of formula (I);
ii) removing any protecting group;
iii) a method of forming a pharmaceutically acceptable salt, solvate, solvate or prodrug of said salt.
[11" claim-type="Currently amended] 10. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof according to any one of claims 1 to 9 for use as a medicament.
[12" claim-type="Currently amended] 10. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, solvent of said salt for use in the prophylactic or therapeutic treatment method of a warm blooded animal such as a human Cargo or prodrug.
[13" claim-type="Currently amended] A compound of formula (I) or a pharmaceutically acceptable salt, solvate, or solvent of said salt of claim 1 in the manufacture of a medicament for use in generating an IBAT inhibitory effect in a warm blooded animal such as human Use of cargo or prodrugs.
[14" claim-type="Currently amended] 10. The method according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, in the development of an IBAT inhibitory effect in warm blooded animals such as humans. Usage.
[15" claim-type="Currently amended] A method of generating an IBAT inhibitory effect in a warm blooded animal, such as a human, comprising: an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate of any one of claims 1 to 9 in said animal in need of such treatment; , Administering a solvate or prodrug of said salt.
[16" claim-type="Currently amended] A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, solvate or prodrug of said salt of any one of claims 1 to 9 together with a pharmaceutically acceptable diluent or carrier.
[17" claim-type="Currently amended] 10. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, solvate or prodrug of said salt and a HMG Co-A reductase inhibitor or pharmaceutically acceptable salt thereof of any one of claims 1 to 9 , Solvates, solvates or prodrugs of said salts with a pharmaceutically acceptable diluent or carrier.
[18" claim-type="Currently amended] A compound of formula (I) or a pharmaceutically acceptable salt, solvate, solvate or prodrug of said salt and bile acid binder of any one of claims 1 to 9 together with a pharmaceutically acceptable diluent or carrier Pharmaceutical composition.
[19" claim-type="Currently amended] A compound of formula (I) or a pharmaceutically acceptable salt, solvate, solvate or prodrug of said salt, a HMG Co-A reductase inhibitor or a pharmaceutically acceptable salt thereof, as claimed in claim 1. , Solvates, solvates or prodrugs of said salts, and bile acid binders, together with a pharmaceutically acceptable diluent or carrier.
[20" claim-type="Currently amended] 20. The composition of claim 17 or 19, wherein the HMG Co-A reductase inhibitor is atorvastatin or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof.
[21" claim-type="Currently amended] 20. The composition of claim 17 or 19, wherein the HMG Co-A reductase inhibitor is rosuvastatin or a pharmaceutically acceptable salt thereof.
[22" claim-type="Currently amended] 10. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, solvate or prodrug of said salt and a PPAR alpha and / or gamma agonist or pharmaceutically acceptable compound of any one of claims 1 to 9 A pharmaceutical composition comprising a salt together with a pharmaceutically acceptable diluent or carrier.
[23" claim-type="Currently amended] The method of claim 22, wherein the PPAR alpha and / or gamma agonist is (S) -2-ethoxy-3- [4- (2- {4-methanesulfonyloxyphenyl} ethoxy) phenyl] propanoic acid or The composition is a pharmaceutically acceptable salt.

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同族专利:

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公开号 | 公开日

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GB0121621D0|2001-10-31|

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US20050032776A1|2005-02-10|

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ES2337559T3|2010-04-27|

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MXPA04002189A|2004-06-29|

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NZ531797A|2005-11-25|

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WO2003022825A1|2003-03-20|

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ZA200401796B|2005-04-08|

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CA2459457A1|2003-03-20|

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JP2005503401A|2005-02-03|

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AT454379T|2010-01-15|

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EP1427713A1|2004-06-16|

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AU2002331927B2|2008-02-21|

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CN1639140A|2005-07-13|

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US7125864B2|2006-10-24|

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UY27437A1|2003-04-30|

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DE60235019D1|2010-02-25|

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NO20040954L|2004-03-04|

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EP1427713B1|2010-01-06|

---

IL160689D0|2004-08-31|

---

BR0212344A|2004-10-19|

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JP4494780B2|2010-06-30|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2001-09-07|Priority to GBGB0121621.7A

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2001-09-07|Priority to GB0121621.7

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2002-09-05|Application filed by 아스트라제네카 아베

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2002-09-05|Priority to PCT/GB2002/004043

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2004-04-09|Publication of KR20040031057A

优先权:

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申请号 | 申请日 | 专利标题

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GBGB0121621.7A|GB0121621D0|2001-09-07|2001-09-07|Chemical compounds|

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GB0121621.7|2001-09-07|

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PCT/GB2002/004043|WO2003022825A1|2001-09-07|2002-09-05|Benzothiazepine derivatives for the treatment of hyperlipidemia|