CA2539032A1 - Glucopyranosyloxy-pirazoles, drugs containing said compounds the use and production method thereof - Google Patents
Glucopyranosyloxy-pirazoles, drugs containing said compounds the use and production method thereof Download PDFInfo
- Publication number
- CA2539032A1 CA2539032A1 CA002539032A CA2539032A CA2539032A1 CA 2539032 A1 CA2539032 A1 CA 2539032A1 CA 002539032 A CA002539032 A CA 002539032A CA 2539032 A CA2539032 A CA 2539032A CA 2539032 A1 CA2539032 A1 CA 2539032A1
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- Prior art keywords
- alkyl
- denotes
- group
- yloxy
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 119
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 7
- 239000003814 drug Substances 0.000 title description 3
- 229940079593 drug Drugs 0.000 title description 2
- 150000003839 salts Chemical class 0.000 claims abstract description 51
- 239000000203 mixture Substances 0.000 claims abstract description 38
- 102000000070 Sodium-Glucose Transport Proteins Human genes 0.000 claims abstract description 13
- 108010080361 Sodium-Glucose Transport Proteins Proteins 0.000 claims abstract description 13
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 8
- 201000010099 disease Diseases 0.000 claims abstract description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 8
- 208000030159 metabolic disease Diseases 0.000 claims abstract description 8
- 150000007524 organic acids Chemical class 0.000 claims abstract description 4
- 235000005985 organic acids Nutrition 0.000 claims abstract description 4
- 150000007522 mineralic acids Chemical class 0.000 claims abstract description 3
- -1 tetrahydrofuran-3-yl Chemical group 0.000 claims description 177
- 229910052739 hydrogen Inorganic materials 0.000 claims description 52
- 239000001257 hydrogen Substances 0.000 claims description 52
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 34
- 229910052731 fluorine Inorganic materials 0.000 claims description 31
- 239000011737 fluorine Substances 0.000 claims description 30
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 27
- 125000001153 fluoro group Chemical group F* 0.000 claims description 26
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 26
- 239000008194 pharmaceutical composition Substances 0.000 claims description 21
- 239000000460 chlorine Chemical group 0.000 claims description 20
- 229910052801 chlorine Inorganic materials 0.000 claims description 20
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
- 229910052794 bromium Inorganic materials 0.000 claims description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims description 13
- 239000000126 substance Substances 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 12
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 12
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 11
- 230000002401 inhibitory effect Effects 0.000 claims description 11
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 11
- 102100037202 Sodium/myo-inositol cotransporter 2 Human genes 0.000 claims description 10
- 101710090560 Sodium/myo-inositol cotransporter 2 Proteins 0.000 claims description 10
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 10
- 230000002265 prevention Effects 0.000 claims description 10
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 7
- 239000003085 diluting agent Substances 0.000 claims description 7
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 7
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 7
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 claims description 7
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 claims description 7
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- 239000000969 carrier Substances 0.000 claims description 6
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 5
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims description 5
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 5
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- 230000010933 acylation Effects 0.000 claims description 4
- 238000005917 acylation reaction Methods 0.000 claims description 4
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 4
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 4
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 4
- 239000002934 diuretic Substances 0.000 claims description 4
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000001041 indolyl group Chemical group 0.000 claims description 4
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims description 4
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- 201000001320 Atherosclerosis Diseases 0.000 claims description 3
- 206010007558 Cardiac failure chronic Diseases 0.000 claims description 3
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 3
- 208000008589 Obesity Diseases 0.000 claims description 3
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 239000002220 antihypertensive agent Substances 0.000 claims description 3
- 229940030600 antihypertensive agent Drugs 0.000 claims description 3
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
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- 229940030606 diuretics Drugs 0.000 claims description 3
- 125000001207 fluorophenyl group Chemical group 0.000 claims description 3
- 235000020824 obesity Nutrition 0.000 claims description 3
- 125000006223 tetrahydrofuranylmethyl group Chemical group 0.000 claims description 3
- 125000006173 tetrahydropyranylmethyl group Chemical group 0.000 claims description 3
- 208000010444 Acidosis Diseases 0.000 claims description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 2
- 208000032928 Dyslipidaemia Diseases 0.000 claims description 2
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- 208000013016 Hypoglycemia Diseases 0.000 claims description 2
- 206010022489 Insulin Resistance Diseases 0.000 claims description 2
- 208000007976 Ketosis Diseases 0.000 claims description 2
- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 2
- 206010027417 Metabolic acidosis Diseases 0.000 claims description 2
- 206010030113 Oedema Diseases 0.000 claims description 2
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 2
- 150000003855 acyl compounds Chemical class 0.000 claims description 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 2
- 125000004104 aryloxy group Chemical group 0.000 claims description 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 2
- 208000018914 glucose metabolism disease Diseases 0.000 claims description 2
- 230000035879 hyperinsulinaemia Effects 0.000 claims description 2
- 230000004140 ketosis Effects 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 12
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 9
- 150000002431 hydrogen Chemical class 0.000 claims 9
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 8
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 3
- 125000006702 (C1-C18) alkyl group Chemical group 0.000 claims 2
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims 2
- 125000006698 (C1-C3) dialkylamino group Chemical group 0.000 claims 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 1
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- 125000006576 di-(C1-C3-alkyl)-aminocarbonyl group Chemical group 0.000 claims 1
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- 229920001223 polyethylene glycol Polymers 0.000 description 1
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- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 1
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- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000003881 protein kinase C inhibitor Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
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- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 229960002354 repaglinide Drugs 0.000 description 1
- 229960004586 rosiglitazone Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910001958 silver carbonate Inorganic materials 0.000 description 1
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 1
- 229960002855 simvastatin Drugs 0.000 description 1
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 1
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- 229960000651 tasosartan Drugs 0.000 description 1
- ADXGNEYLLLSOAR-UHFFFAOYSA-N tasosartan Chemical compound C12=NC(C)=NC(C)=C2CCC(=O)N1CC(C=C1)=CC=C1C1=CC=CC=C1C=1N=NNN=1 ADXGNEYLLLSOAR-UHFFFAOYSA-N 0.000 description 1
- 229960005187 telmisartan Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
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- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/02—Heterocyclic radicals containing only nitrogen as ring hetero atoms
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Abstract
The invention relates to glucopyranosyloxy-pirazoles of formula (I), wherein R1 to R6 and R7a, R7b and R7c are defined in the claim 1, to the tautomers, stereoisomers, mixtures and the salts thereof, in particular the salts which are physiologically compatible with inorganic or organic acids and exhibit interesting pharmacological properties, in particular inhibitor effect on a sodium-dependent SGLT glucose cotransporter. The use of the inventive compounds for treating diseases, in particular metabolic diseases such as diabetes and the production thereof are also disclosed.
Description
Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff 85111 fft Glucopyranosyloxy-pyrazoles, pharmaceutical compositions containing these compounds, the use thereof and processes for the preparation thereof The present invention relates to glucopyranosyloxy-pyrazoles of general formula I
R \ R2 N
N \~ Rs RIO O O
R'a0~~~, ~~~~OR'c OR'b (I), wherein the groups R' to R6 and R'a, R'b, R'° are defined hereinafter, including the tautomers, the stereoisomers, the mixtures thereof and the salts thereof. The invention also relates to pharmaceutical compositions containing a compound of formula I
according to the invention as well as the use of a compound according to the invention for preparing a pharmaceutical composition for the treatment of metabolic disorders.
Processes for preparing a pharmaceutical composition and a compound according to the invention are also the subject of this invention.
In the literature, compounds which have an inhibitory effect on the sodium-dependent glucose cotransporter SGLT2 are proposed for the treatment of diseases, particularly diabetes.
Glucopyranosyloxy-pyrazole derivatives and the preparation thereof and their possible activity as SGLT2 inhibitors are known from published International applications WO
02/36602, WO 02/088157, WO 01/16147, WO 02/053573, WO 02/068439, WO
02/068440 and WO 02/098893.
Boehringer Ingeltlelnl CA 02539032 2006-02-24 Case 1/1558 ff Aimi of the invention The aim of the present invention is to find new glucopyranosyloxy-pyrazole derivatives, particularly those which are active with regard to the sodium-dependent glucose cotransporter SGLT, particularly SGLT2. A further aim of the present invention is to discover glucopyranosyloxy-pyrazole derivatives which have an enhanced inhibitory effect on the sodium-dependent glucose cotransporter SGLT2 in vitro and/or in vivo compared with known, structurally similar glucopyranosyloxy-pyrazoles and/or have better pharmacological properties.
A further aim of the present invention is to provide new pharmaceutical compositions which are suitable for the prevention and/or treatment of metabolic disorders, particularly diabetes.
The invention also sets out to provide a process for preparing the compounds aca~rding to the invention.
Other aims of the present invention will become apparent to the skilled man directly from the foregoing and following remarks.
Object of the invention In a first aspect the present invention relates to glucopyranosyloxy-pyrazoles of general formula I
RIO
R
OR'° (I).
wherein B0211f1ng2~ IngelhelfTl CA 02539032 2006-02-24 Cage 1/1558 ff R' denotes C3_6-alkynyl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuranyl-C,_3-alkyl, tetrahydropyranyl-C,_3-alkyl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, or a pyrrolidin-3-yl, piperidin-3-yl or piperidin-4-yl group, while in the latter three groups the nitrogen atom may be substituted by a C~_4-alkyl, formyl, C»-alkyl-carbonyl, C~_4-alkylsulphonyl, cyano, aminocarbonyl, (C~_4-alkyl)-aminocarbonyl, di-(C»-alkyl)-aminocarbonyl or (C~.~-alkyl)-oxycarbonyl group, or if R3 (a) is selected from one of the definitions of the group A; or (b) together with R4 denotes difluoromethylenedioxy; or (c) denotes C3~-cycloalkyl-oxy or C3~-cycloalkylidene-methyl and simultaneously R4 denotes fluorine, chlorine, bromine, C~_3-alkyl, C~_3-alkoxy or a methyl or methoxy group substituted by 1 to 3 fluorine atoms;
then R' may also represent hydrogen, C~_s-alkyl, a C»-alkyl group substituted by 1 to 3 fluorine atoms, a C2~-alkyl group substituted by a hydroxy or C~_3-alkoxy group, or C3~-alkenyl, C3~-cycloalkyl, C~-cycloalkyl-C~_3-alkyl, aryl or aryl-C~_3-alkyl, and R2 denotes C~_4-alkyl, a C~~-alkyl group substituted by 1 to 3 fluorine atoms, or C3_s-cycloalkyl, and R3 denotes hydrogen, fluorine, chlorine, bromine, iodine, C»-alkyl, C2~-alkenyl, C2_6-alkynyl, C3_s-cycloalkyl, C3_6-cycloalkylidenemethyl, C~~-alkoxy, C3_s-cycloalkyl-oxy, C~s-cycloalkyl-C~_3-alkoxy, aryl, aryl-C,_3-alkyl, heteroaryl, heteroaryl-C~_3-alkyl, aryloxy, aryl-C,_3-alkyl-oxy, a methyl or methoxy group substituted by 1 to 3 fluorine atoms, a C2~-alkyl or C2~-alkoxy group substituted by 1 to 5 fluorine atoms, a C~~-alkyl group substituted by a cyano group, a C,_4_alkyl group substituted by a hydroxy or C~_3-alkyloxy group, or cyano, carboxy, C~_3-alkoxycarbonyl, aminocarbonyl, Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff (C~_3-alkylamino)carbonyl, di-(C~_3-alkyl)aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-yl-carbonyl, 4-(C~-alkyl)-piperazin-1-ylcarbonyl, nitro, amino, Ci_3-alkylamino, di-(C~_3-alkyl)amino, (C~_4-alkyl)carbonylamino, C~_4-alkylsulphonylamino, arylsulphonylamino, aryl-C~_3-alkylsulphonylamino, C»-alkylsulphanyl, C~_4-alkylsulphinyl, C~_4-alkylsulphonyl, arylsulphenyl, arylsulphinyl or arylsulphonyl, or has a meaning selected from the group A, and R4 and R5, which may be identical or different, represent hydrogen, fluorine, chlorine, bromine, C~_3-alkyl, C~_3-alko;y, a methyl or methoxy group substituted by 1 to 3 fluorine atoms, or R3 together with R4, if they are bound to adjacent carbon atoms, may also represent a straight-chain C3_5-alkylene, a methylenedioxy or difluoromethylenedioxy bridge, and Rs ~ Rya R'b, R'° independently of one another have a meaning selected from the group hydrogen, (C~_~8-alkyl)carbonyl, (C~_~$-alkyl)oxycarbonyl, arylcarbonyl and aryl-(C~_3-alkyl)-carbonyl, A is selected from the group consisting of tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl-C~_3-alkoxy, tetrahydropyranyl-C~_3-alkoxy, pyrrolidin-3-yloxy, piperidin-3-yloxy, piperidin-4-yloxy group, and pyrrolidin-3-yloxy, piperidin-3-yloxy- and piperidin-4-yloxy, while in the latter three groups the nitrogen atom may be substituted by C~_4-alkyl, formyl, C~_4-alkyl-carbonyl, C,_4-alkylsulphonyl, cyano, aminocarbonyl, (C,_4-alkyl)-aminocarbonyl, di-(C~_4-alkyl)-aminocarbonyl or (C,~-alkyl)-oxycarbonyl, whilE: the aryl groups mentioned in the definition of the above groups are meant to indicate phenyl or naphthyl groups which may be mono- or disubstituted independently Boehringer Ingeltlellll CA 02539032 2006-02-24 Case 1/1558 ff of one another by R,,, while the substituents may be identical or different and R,, denotes a fluorine, chlorine, bromine, iodine, C~_3-alkyl, difluoromethyl, trifluoromethyl, C~_3-alkoxy, difluoromethoxy, trifluoromethoxy or cyano, the Iheteroaryl groups mentioned in the definition of the above-mentioned groups are meant to indicate a pyrrolyl, furanyl, thienyl, pyridyl, indolyl, benzofuranyl, benzothio-phenyl, quinolinyl or isoquinolinyl group, or a pyrrolyl, furanyl, thienyl or pyridyl group, wherein one or two methyne groups are replaced by nitrogen atoms, or an indolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl group, wherein one to three methyne groups are replaced by nitrogen atoms, while the above-mentioned heteroaryl groups may be mono- or disubstituted by R,,, while the substituents may be identical or different and Rh is as hereinbefore defined, while, unless otherwise stated, the above-mentioned alkyl groups may be straight-chain or branched, the tautomers, the stereoisomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof.
The compounds according to the invention of general formula I and the physiologically accE:ptable salts thereof have valuable pharmacological properties, particularly an inhibitory effect on the sodium-dependent glucose cotransporter SGLT, particularly SGLT2. Moreover compounds according to the invention may have an inhibitory effect on the sodium-dependent glucose cotransporter SGLT1. Compared with a possible inhibitory effect on SGLT1 the compounds according to the invention preferably inhibit SGLT2 selectively.
The present invention also relates to the physiologically acceptable salts of the comlpounds according to the invention with inorganic or organic acids.
Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff Therefore, the invention also relates to the use of the compounds according to the invention, including the physiologically acceptable salts, as pharmaceutical compositions.
This invention also relates to pharmaceutical compositions, containing at least one compound according to the invention or a physiologically acceptable salt according to the invention, optionally together with one or more inert carriers and/or diluents.
A further subject of this invention is the use of at least one compound according to the invention or a physiologically acceptable salt of such a compound for preparing a pharmaceutical composition which is suitable for the treatment or prevention of diseases or conditions which can be influenced by inhibiting the sodium-dependent glucose cotransporter SGLT, particularly SGLT2.
This; invention also relates to the use of at least one compound according to the invention for preparing a pharmaceutical composition which is suitable for the treatment of metabolic disorders.
This, invention also relates to the use of at least one compound according to the invention for preparing a pharmaceutical composition for inhibiting the sodium-dep~endent glucose cotransporter SGLT, particularly SGLT2.
The invention further relates to a process for preparing a pharmaceutical composition according to the invention, characterised in that a compound according to the invention is incorporated in one or more inert carriers and/or diluents by a non-chemical method.
The present invention also relates to a process for preparing the compounds according to the invention of general formula I, characterised in that a) in order to prepare compounds of general formula I wherein R' is as here~inbefore defined, but does not denote hydrogen, Boehringer Ingelhelfll CA 02539032 2006-02-24 Case 111558 ff a compound of general formula ~5 RIO O O
R'a0~~~, I~~~OR'c OR'b (II), wherein R2 to R6 and R'a, R'b, R'c are as hereinbefore defined, is reacted with a compound of general formula Z' - R'~ (III), wherein R'~ has the meanings given for R' hereinbefore, but does not denote a hydrogen atom, and Z' denotes a leaving group, or b) in order to prepare compounds of general formula I wherein R3 denotes optionally substituted C~_6-alkoxy, C3_s-cycloalkyl-oxy, C3_5-cycloalkyl-C~_3-alkoxy or a meaning selected from the group A, which is as hereinbefore defined, a compound of general formula Boeriringer Ingelllelnl CA 02539032 2006-02-24 Case 1/1558 ff _g_ RIO
R
OR'° (IV), wherein R', 1~2 and R4 to Rs as well as R'a, R'b, R'° are as hereinbefore defined, is reacted with a compound of general formula Z2 _ Rs, (V), wherein R3~ denotes optionally substituted C~_6-alkoxy, C3~-cycloalkyl-oxy, C~5-cycloalkyl-C~_3-alko:xy or a meaning selected from the group A, which is as hereinbefore defined, and Z2 denotes a leaving group, preferably a halogen atom, for example a chlorine or bromine atom, a sulphonyloxy group, for example a methanesulphonyloxy or p-toluE;nesulphonyloxy group or a hydroxy group, and after step a) or b) has been carried out, if desired a compound of general formula I
thus obtained wherein Rs denotes a hydrogen atom, is converted by acylation into a corrEaponding acyl compound of general formula I, and/or if necessary a protecting group used during the reactions described above is cleaved again and/or if desired a compound of general formula I thus obtained is separated into its stere~oisomers and/or Boehringer Ingelhelfn CA 02539032 2006-02-24 Case 1/1558 ff _g_ a compound of general formula I thus obtained is converted into the salts thereof, partlicularly for pharmaceutical use into the physiologically acceptable salts thereof.
Detailed Description of the invention Unlf;ss otherwise stated the groups, residues and substituents, particularly R' to Rs and R'a, R'b, R'°, are defined as above and hereinafter.
If residues, substituents or groups occur several times in a compound, they may have the Name or different meanings.
The term aryl used above and hereinafter, for example in the groups R', R3, Rs, R'a R'b , R'°, preferably denotes phenyl. According to the general definition and unless otherwise stated, the aryl group, particularly the phenyl group, may be mono-or disubstituted by identical or different groups Rh.
Compounds according to the invention, in a first embodiment of this invention, may be described by general formula I, wherein R' denotes C3_s-alkynyl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuranyl-C~_3-alkyl, tetrahydropyranyl-C~_3-alkyl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, or a pyrrolidin-3-yl, piperidin-3-yl or piperidin-4-yl group, while in the latter three groups the nitrogen atom may be substituted by a C~_4-alkyl, formyl, C~~-alkyl-carbonyl, C~_4-alkylsulphonyl, cyano, aminocarbonyl, (C~_4-alkyl)-aminocarbonyl, di-(C~_4-alkyl)-aminocarbonyl or (C~_4-alkyl)-oxycarbonyl group, and the other groups R2 to Rs and R'a, R'b, R'' are as hereinbefore defined, including the tautomers, the stereoisomers, the mixtures thereof and the salts thereof.
Preferred meanings of the group R' according to this embodiment are 2-propyn-1-yl, 2-butyn-1-yl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, Boef~iringer Ingelhelfll CA 02539032 2006-02-24 Case 1/1558 ff tetrahydrofuranylmethyl and tetrahydropyranylmethyl. Most particularly preferred meanings are 2-propyn-1-yl, 2-butyn-1-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl-and tetrahydrofuran-2-ylmethyl.
Preferred meanings of the group R3 according to this embodiment are hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, tert.-butyl, 2-cyano-2-propyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, cyclopropyl-oxy, cyclnbutyl-oxy, cyclopentyl-oxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethyloxy, tetrahydropyranyl-methyloxy, methylsu!phanyl, 2-methyl-1-propen-1-yl, cyclopropylidenemethyl, ethynyl, phenyl, fluorophenyl, pyridyl and methylthiazolyl. Most particularly preferred meanings are fluorine, chlorine, methyl, ethyl, isopropyl, tert.-butyl, difluoromethyl, trifluoromethyl, cyclnpropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, particularly ethyl.
Preferred meanings of the group R4 according to this first embodiment are hydrogen and fluorine, particularly hydrogen.
Corrrpounds according to the invention in a second embodiment of this invention may be described by general formula I, wherein R' denotes hydrogen, C~_s-alkyl, C~_4-alkyl substituted by 1 to 3 fluorine atoms, C2_4-alkyl substituted by a hydroxy or C~_3-alkoxy group, C3_6-alkenyl, C~6-cycloalkyl, C3~-cycloalkyl-C,_3-alkyl, aryl or aryl-C,_3-alkyl, and R3 is selected from the group A consisting of tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl-Boeh~ringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff C~_3-alkoxy, tetrahydropyranyl-C~_3-alkoxy, pyrrolidin-3-yloxy, piperidin-3-yloxy, piperidin-4-yloxy group, and pyrrolidin-3-yloxy, piperidin-3-yloxy and piperidin-4-yloxy, while in the latter three groups the nitrogen atom is substituted by C~.~-alkyl, formyl, C~~-alkyl-carbonyl, C~_4-alkylsulphonyl, cyano, aminocarbonyl, (C~_4-alkyl)-aminocarbonyl, di-(C~_4-alkyl)-aminocarbonyl or (C~._4-alkyl)-oxycarbonyl, and the other groups, particularly R2 and R4 to R6 and R'a, R'b, R'° are as hereinbefore defined, including the tautomers, the stereoisomers, the mixtures thereof and the salts thereof.
Preferred meanings of the group R' according to this embodiment are C~_s-alkyl, a C,~,-alkyl group substituted by 1 to 3 fluorine atoms, C3~-cycloalkyl and C~-cycloalkyl-C~_3-alkyl, particularly C~_4-alkyl, which may be substituted by 1 to 3 fluorine atoms, most preferably methyl, ethyl, propyl or butyl, most particularly preferably isopropyl.
Preferred meanings of the group R3 according to this embodiment are tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethyloxy and tetrahydropyranylmethyloxy.
Preferred meanings of the group R4 according to this second embodiment are hydrogen and fluorine, particularly hydrogen.
Compounds according to the invention in accordance with a third embodiment of this invention may be described by general formula I, wherein R' denotes hydrogen, C,_s-alkyl, C~_4-alkyl substituted by 1 to 3 fluorine atoms, C2_4-alkyl substituted by a hydroxy or C~_3-alkoxy group, Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff C3_6-alkenyl, C3~-cycloalkyl, C3~-cycloalkyl-C~_3-alkyl, aryl or aryl-C~_3-alkyl, and R3 together with R4, which are bound to adjacent carbon atoms, denotes a difluoromethylenedioxy bridge, and the other groups, particularly R2, R5 and Rs and R'a, R'b, R'° are as hereinbefore defined, including the tautomers, the stereoisomers, the mixtures thE~eof and the salts thereof Preferred meanings of the group R~ according to this embodiment are C~~-alkyl, a C»-alkyl group substituted by 1 to 3 fluorine atoms, C3~-cycloalkyl and C3_s-cycloalkyl-C~_3-alkyl, particularly C~_4-alkyl, which may be substituted by 1 to 3 fluorine atoms, particularly preferably methyl, ethyl, propyl or butyl, most particularly preferably isopiropyl.
Compounds according to the invention in a fourth embodiment of this invention may be described by general formula I, wherein R' denotes hydrogen, C~~-alkyl, C~~-alkyl substituted by 1 to 3 fluorine atoms, C2_4-alkyl substituted by a hydroxy or C~_3-alkoxy group, C3_6-alkenyl, C3_6-cycloalkyl, C3~-cycloalkyl-C~_3-alkyl, aryl or aryl-C~_3-alkyl, and R3 denotes C3~-cycloalkyl-oxy, and Boeh~ringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff R4 denotes fluorine, chlorine, bromine, C~_3-alkyl, C~_3-alkoxy or a methyl or methoxy group substituted by 1 to 3 fluorine atoms, and the other groups, particularly R2, R5 and Rs as well as R'a, R'b, R'°
are as hereinbefore defined, including the tautomers, the stereoisomers, the mixtures thereof and the salts thereof.
Preferred meanings of the group R' according to this embodiment are C»-alkyl, a C»-alkyl group substituted by 1 to 3 fluorine atoms, C3~-cycloalkyl and C3~-cycloalkyl-C~_3-alkyl, particularly C~_4-alkyl, which may to substituted by 1 to 3 fluorine atoms, particularly preferably methyl, ethyl, propyl or butyl, most particularly preferably isopropyl.
Preferred meanings of the group R3 according to this embodiment are cylopropyloxy, cyclnbutyloxy and cyclopentyloxy.
Preferred meanings of the group R4 according to this embodiment are fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxy and trifluoromethoxy, particularly fluorine.
Corrrpounds according to the invention in a fifth embodiment of this invention may be described by general formula I, wherein R' denotes hydrogen, C»-alkyl, C~_4-alkyl substituted by 1 to 3 fluorine atoms, C2_4-alkyl substituted by a hydroxy or C,_3-alkoxy group, C3~-alkenyl, C3_6-cycloalkyl, C3~-cycloalkyl-C~_3-alkyl, aryl or aryl-C~_3-alkyl, and Boehringer Iflgelhelfll CA 02539032 2006-02-24 Case 1/1558 ff R3 denotes C3_s-cycloalkylidene-methyl, and R4 denotes fluorine, chlorine, bromine, C~_3-alkyl, C~_3-alkoxy or a methyl or methoxy group substituted by 1 to 3 fluorine atoms, and the other groups, particularly R2, R5 and R6 and R'a, R'b, R'° are as hereinbefore defined, incluiding the tautomers, the stereoisomers, the mixtures thereof and the salts thereof Preferred meanings of the group R' according to this embodiment are C»-alkyl, C~~-alkyl substituted by 1 to 3 fluorine atoms, C3~-cycloalkyl and C3~-cycloalkyl-C~_3-alkyl, particularly C~~-alkyl, which may be substituted by 1 to 3 fluorine atoms, particularly prefE;rably methyl, ethyl, propyl or butyl, most particularly preferably isopropyl.
A preferred meaning of the group R3 according to this embodiment is cyclopropylidenemethyl.
Preferred meanings of the group R4 according to this embodiment are fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxy and trifluoromethoxy, particularly fluorine.
The following remarks refer to the compounds of formula I, particularly the first, second, third, fourth and fifth embodiments already mentioned above.
If the; group R~ denotes pyrrolidin-3-yl, piperidin-3-yl or piperidin-4-yl, the nitrogen atom is pr~sferably substituted as specified.
According to an alternative to the embodiments described above, other preferred compounds are those wherein the phenyl group which carries the substituents R3, has at least one other substituent R4 and/or R5 which is not hydrogen. According to this alterinative, particularly preferred compounds are those which have a substituent R4 which is fluorine.
Boehringer Ingelheln'1 CA 02539032 2006-02-24 Case 1/1558 ff Preferred meanings of the group R5 are hydrogen and fluorine.
Preferred meanings of the group R2 according to the invention are methyl and trifluoromethyl, particularly methyl.
The group Rs according to the invention preferably denotes hydrogen, (C~_8-alkyl)oxycarbonyl or C~_8-alkylcarbonyl, particularly H or (C~~-alkyl)oxycarbonyl, particularly preferably H, methoxycarbonyl or ethoxycarbonyl.
The substituents R'a, R'b, R'° independently of one another preferably represent hydrogen or (C~_~$-alkyl)carbonyl, particularly hydrogen or (C~_$-alkyl)carbonyl, particularly preferably hydrogen, methylcarbonyl or ethylcarbonyl. Most preferably, R'a, R'b <~nd R'° represent hydrogen.
The compounds of formula I wherein Rs, R'a, R'b and R'° have a meaning according to the invention other than H, for example C~_8-alkylcarbonyl, are preferred as intermediate products for the synthesis of compounds of formula I wherein R'a, R'b and R'' represent hydrogen.
According to the invention compounds of general formula I are preferred wherein R' denotes 2-propyn-1-yl, 2-butyn-1-yl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuranylmethyl or tetrahydropyranylmethyl, or, if R3 (a) is selected from the group consisting of tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethyloxy and tetrahydropyranylmethyloxy, or (b) together with R4 denotes a difluoromethylenedioxy bridge, or, (c) denotes cylopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclopropylidenemethyl and R4 simultaneously denotes fluorine, then R' may also represent isopropyl, and Boehringer Ingelhelftl CA 02539032 2006-02-24 Case 1/1558 ff R2 denotes methyl or trifluoromethyl, R3 denotes hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, tert.-butyl, 2-cyano-2-propyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, cylopropyl-oxy, cyclobutyl-oxy, cyclopentyl-oxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethyloxy, tetrahydropyranylmethyloxy, methylsulphanyl, 2-methyl-1-propen-1-yl, cyclopropylidenemethyl, ethynyl, phenyl, fluorophenyl, pyridyl or methylthiazolyl, and R4 denotes hydrogen or fluorine, or R3 together with R4, if they are bound to adjacent carbon atoms, may also represent a 1,3-propylene, methylenedioxy or difluoromethylenedioxy bridge, and R5 denotes hydrogen and Rs denotes hydrogen, (C~_$-alkyl)oxycarbonyl or C~_$-alkylcarbonyl, the tautomers, the stereoisomers, the mixtures thereof and the salts thereof.
According to the invention compounds of general formula I are particularly preferred wherein R' denotes 2-propyn-1-yl, 2-butyn-1-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl or tetrahydrofuran-2-ylmethyl or, if R3 is selected from the group consisting of tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy and tetrahydrofuranylmethyloxy, then R' may also represent isopropyl, Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff R2 denotes methyl, R3 denotes methyl, ethyl, methoxy, ethoxy, difluoromethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy or tetrahydrofuranylmethyloxy, R4 denotes hydrogen or fluorine RS denotes hydrogen and Rs denotes hydrogen, methoxycarbonyl or ethoxycarbonyl, the i:automers, the stereoisomers, the mixtures thereof and the salts thereof.
According to the invention compounds of general formula I are most particularly preferred, wherein R' denotes tetrahydrofuran-3-yl or tetrahydropyran-4-yl, R2 denotes methyl, R3 denotes methyl, ethyl, methoxy, ethoxy or difluoromethoxy, R4 denotes hydrogen or fluorine, RS denotes hydrogen, R6 denotes hydrogen, methoxycarbonyl or ethoxycarbonyl and R'a, R'b and R'° represent hydrogen, the tautomers, the stereoisomers, the mixtures thereof and the salts thereof.
Parl:icularly preferred compounds of general formula I are selected from the group (a) 1-(2-propyn-1-yl)-3-(f3-D-glucopyranosyloxy)-4-(4-ethylbenzyl)-5-methyl-1 H-pyrazole (b) 1-(2-propyn-1-yl)-3-(6-O-methoxycarbonyl-f3-D-glucopyranosyloxy)-4-(4-ethylbenzyl)-5-methyl-1 H-pyrazole (c) 1-((S)-tetrahydrofuran-3-yl)-3-(f3-D-glucopyranosyloxy)-4-(4-ethylbenzyl)-methyl-1 H-pyrazole Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff (d) 1-(tetrahydropyran-4-yl)-3-(f3-D-glucopyranosyloxy)-4-(4-ethylbenzyl)-5-methyl-1 H-pyrazole, (e) 1-isopropyl-3-(f3-D-glucopyranosyloxy)-4-[4-((S)-tetrahydrofuran-3-yloxy)benzyl]-5-mEahyl-1 H-pyrazole (f) 1-isopropyl-3-(f3-D-glucopyranosyloxy)-4-[4-((R)-tetrahydrofuran-3-yloxy)benzyl]-5-methyl-1 H-pyrazole, (g) 1-(tetrahydropyran-4-yl)-3-(f3-D-glucopyranosyloxy)-4-(4-methoxybenzyl)-5-methyl-1 H-pyrazole, and the derivatives thereof, wherein Rs has a meaning according to the invention other than hydrogen, and in particular Rs denotes ethoxycarbonyl or methoxycarbonyl, including the tautomers, the stereoisomers, the mixtures thereof and the salts thereof.
Some terms used above and hereinafter to describe the compounds according to the invention will now be defined more closely.
The term halogen denotes an atom selected from the group consisting of F, CI, Br and I, particularly F, CI and Br.
The term C~_~-alkyl, wherein n may have a value of 2 to 8, denotes a saturated, branched or unbranched hydrocarbon group with 1 to n C atoms. examples of such groups include methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, tert-pentyl, n-hexyl, iso-hexyl, etc..
The term C,_~-alkylene, wherein n may have a value of 2 to 8, denotes a saturated, branched or unbranched hydrocarbon bridge with 1 to n C atoms. Examples of such groups include methylene (-CH2-), ethylene (-CH2-CH2-), 1-methyl-ethylene (-CH(CH3)-CH2-), 1,1-dimethyl-ethylene (-C(CH3)2-CH2-), n-prop-1,3-ylene (-CH2-Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff CH2-), 1-methylprop-1,3-ylene (-CH(CH3)-CH2-CH2-), 2-methylprop-1,3-ylene (-CH(CH3)-CH2-), etc., as well as the corresponding mirror-symmetrical forms.
The term C2_~ alkenyl, wherein n has a value of 3 to 6, denotes a branched or unbranched hydrocarbon group with 2 to n C atoms and a C=C-double bond.
Examples of such groups include vinyl, 1-propenyl, 2-propenyl, iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, perntenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl etc..
The term C~~ ~-alkynyl, wherein n has a value of 3 to 6, denotes a branched or unbranched hydrocarbon group with 2 to n C atoms and a C--_C triple bond.
Examples of such groups include ethynyl, 1-propynyl, 2-propynyl, iso-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 2-methyl-1-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 3-methyl-2-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl; 5-hexynyl etc.:
The term C~_~-alkoxy or C~_~-alkyloxy denotes a C~_~ alkyl-O group, wherein C1_"-alkyl is as hereinbefore defined. Examples of such groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, iso-pentoxy, neo-pentoxy, tert-pentoxy, n-hexoxy, iso-hexoxy etc..
They term C~_~-alkylcarbonyl denotes a C~_~ alkyl-C(=O) group, wherein C~_~-alkyl is as herninbefore defined. Examples of such groups include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, iso-propylcarbonyl, n-butylcarbonyl, iso-butylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, iso-pentylcarbonyl, neo-pen~tylcarbonyl, tert-pentylcarbonyl, n-hexylcarbonyl, iso-hexylcarbonyl, etc..
The: term C3_~-cycloalkyl denotes a saturated mono-, bi-, tri- or spirocarbocyclic group with 3 to n C atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, bicyclo[3.2.1.]octyl, spiro[4.5]decyl, norpinyl, norbonyl, norcaryl, adamantyl, etc..
Preferably the term C3_~-cycloalkyl denotes saturated monocyclic groups.
Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff The term C5_~-cycloalkenyl denotes a monounsaturated mono-, bi-, tri- or spirocarbocyclic group with 5 to n C atoms. Examples of such groups include cycl~opentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, etc.
The term C~~-cycloalkyloxy denotes a C3_n-cycloalkyl-O group, wherein C~~
cycloalkyl is as hereinbefore defined. Examples of such groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, etc.
The term C3_~-cycloalkylcarbonyl denotes a C~~ cycloalkyl-C(=O) group, wherein C3_n-cycloalkyl is as hereinbefore defined.
The style used above and hereinafter, in which a bond of a substituent in a phenyl group is shown towards the centre of the phenyl ring, denotes, unless otherwise stated, that this substituent may be bound to any free position of the phenyl ring bearing an H atom.
The compounds according to the invention may be obtained using methods of synthesis known in principle. Preferably the compounds are obtained by the following methods according to the invention which are described in more detail hereinafter.
a) In order to prepare compounds of general formula I wherein R' is as her~~inbefore defined, but does not denote a hydrogen atom:
reacting a compound of general formula H
r N
RIO O O
R~aO,~~ ''~,OR~c OR'b (II), wherein Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff R2 t~o R6 as well as R'a, R'b, R'° are as hereinbefore defined, with a compound of general formula Z' - R'~ (III), wherein R'~ has the meanings given for R' hereinbefore, but does not denote a hydrogen atom, and Z' denotes a leaving group, preferably a halogen atom, for example a chlorine or bromine atom, a sulphonyloxy group, for example a methane::ulphonyloxy or p-toluenesulphonyloxy group or a hydroxy group.
The reaction is conveniently carried out in a solvent, such as for example acetonitrile, toluene, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulphoxide or N-methylpyrrolidinone, optionally in the presence of a base, such as for example potassium carbonate, caesium carbonate, sodium hydride or potassium-tert.-butoxide, at temperatures between 20°C and 160°C.
With a compound of general formula III, wherein Z' denotes a hydroxy group, the reaction is carried out in the presence of a dehydrating agent, preferably in the presence of a phosphine and an azodicarboxylic acid derivative such as e.g.
triphenylphosphine/diethyl azodicarboxylate, conveniently in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, dioxane, toluene or ethyleneglycoldiethylether or mixtures thereof at temperatures between -50 and 150°C, but preferably at temperatures between -20 and 80°C.
b) In order to prepare compounds of general formula I wherein R3 denotes optionally substituted C~_s-alkoxy, C3_6-cycloalkyl-oxy, C3_5-cycloalkyl-C~_3-alkoxy or a meaning selected from the group A, which is as hereinbefore defined:
reacting a compound of general formula Boef~iringer Ingelhelfl'1 CA 02539032 2006-02-24 Case 1/1558 ff )H
R' P
RIO O O
R7a0,~~ ''~, OR7c OR'b (IV), wherein R', R2 and R4 to R6 and R'a, R'b, R'c are as hereinbefore defined, with a compound of general formula Z2 _ Rs. (V), wherein R3~ denotes optionally substituted C~_s-alkoxy, C~-cycloalkyl-oxy, C~5-cycloalkyl-C~_3-alkc~xy or a meaning selected from the group A, which is as hereinbefore defined, and Z2 denotes a leaving group, preferably a halogen atom, for example a chlorine or brornine atom, a sulphonyloxy group, for example a methanesulphonyloxy or p-toluenesulphonyloxy group or a hydroxy group.
The reaction is conveniently carried out in a solvent, such as for example acetonitrile, toluene, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulphoxide or N-methylpyrrolidinone, optionally in the presence of a base, such as for example potassium carbonate, caesium carbonate, sodium hydride or potassium-tert.-butoxide, at temperatures between 20°C and 160°C.
With a compound of general formula V, wherein Z2 denotes a hydroxy group, the rea<;tion is carried out in the presence of a dehydrating agent, preferably in the presence of a phosphine and an azodicarboxylic acid derivative such as e.g.
triphenylphosphine/diethyl azodicarboxylate, conveniently in a solvent such as Boehringer Ingelhe11T1 CA 02539032 2006-02-24 Case 1/1558 ff methylene chloride, acetonitrile, tetrahydrofuran, dioxane, toluene or ethyleneglycoldiethylether or mixtures thereof at temperatures between -50 and 150°C, but preferably at temperatures between -20 and 80°C.
If according to the invention a compound of general formula I is obtained wherein R6 denotes a hydrogen atom, this may be converted by acylation, for example by acylation in the presence of a base such as pyridine, collidine, triethylamine or N-ethyl-diisopropylamine, into a compound wherein Rs denotes a (C~_,8-alkyl)carbonyl group, a (C~_,8-alkyl)oxycarbonyl group, an arylcarbonyl group or an aryl-(C~_3-alkyl)-carbonyl group. Suitable acylating agents may be, in particular, the corresponding activated acyl derivatives such as acid chlorides or anhydrides.
In the reactions described hereinbefore, any reactive groups present such as hydroxy, amino, alkylamino or imino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.
For example, a protecting group for a hydroxy group may be a trimethylsilyl, acetyl, benzyl or tetrahydropyranyl group, proi:ecting groups for an amino, alkylamino or imino group may be, for example, a formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group.
Any protecting group used is optionally subsequently cleaved for example by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, acetic acid/water, tetr,ahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali mei:al base such as lithium hydroxide, sodium hydroxide or potassium hydroxide or aprotically, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 12Ci°C, preferably at temperatures between 10 and 100°C.
However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved, for example, hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethyl acetate or Boehringer IngeItleIrT1 CA 02539032 2006-02-24 Case 1/1558 ff glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100°C, but preferably at ambient temperatures between 20 and 60°C, and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar. A
2,4-~dimethoxybenzyl group, however, is preferably cleaved in trifluoroacetic acid in the presence of anisole.
A te:rt.butyl or tert.butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid or by treating with iodotrimethylsilane optionally using a solvent such as methylene chloride, dioxane, methanol or diethylether.
A trifluoroacetyl group is preferably cleaved by treating with an acid such as hydrochloric acid, optionally in the presence of a solvent such as acetic acid at temperatures between 50 and 120°C or by treating with sodium hydroxide solution optionally in the presence of a solvent such as tetrahydrofuran or methanol at temperatures between 0 and 50°C.
Moreover, the compounds of general formula I obtained may be resolved into their enantiomers and/or diastereomers, as mentioned hereinbefore. Thus, for example, cisl'trans mixtures may be resolved into their cis and trans isomers, and compounds with at least one optically active carbon atom may be separated into their enantiomers.
Thus, for example, the cisltrans mixtures may be resolved by chromatography into the cis and trans isomers thereof, the compounds of general formula I obtained which occur as racemates may be separated by methods known per se (cf. Allinger N.
L. and EIiE;I E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971 ) into their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.
ThE: enantiomers are preferably separated by column separation on chiral phases or by irecrystallisation from an optically active solvent or by reacting with an optically Boehringer IflgelhelfTl CA 02539032 2006-02-24 Case 1/1558 ff active substance which forms salts or derivatives such as e.g. esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Optically active acids in common use are e.g. the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. An optically active alcohol may be for example (+) or (-menthol and an optically active acyl group in amides, for example, may be a (+~or (-)-menthyloxycarbonyl.
Furthermore, the compounds of formula I may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts with inorcaanic or organic acids. Acids which may be used for this purpose include for exarnple hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or malefic acid.
Morf:over, the compounds obtained may be converted into mixtures, for example 1:1 or 1:2 mixtures with amino acids, particularly with alpha-amino acids such as proline or phenylalanine, which may have particularly favourable properties such as a high crystallinity.
The .compounds of general formulae I I to V used as starting materials are partly known from the literature or may be obtained by methods known from the literature {see Examples I to VI), optionally with the additional inclusion of protecting groups.
The compounds according to the invention may advantageously also be obtained by the methods described in the following examples, which may also be combined with methods known to the skilled man from the literature, for example, particularly the methods described in WO 02/36602, WO 02/088157, WO 01/16147, WO 02/053573, WO 021068439, WO 02/068440 and WO 02/098893.
Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff As already mentioned, the compounds of general formula I according to the invention and the physiologically acceptable salts thereof have valuable pharmacological properties, particularly an inhibitory effect on the sodium-dependent glucose cotransporter SGLT, preferably SGLT2.
The biological properties of the new compounds may be investigated as follows:
The ability of the substances to inhibit the SGLT-2 activity may be demonstrated in a test set-up in which a CHO-K1 cell line (ATCC No. CCL 61 ) or alternatively an cell line (ATCC No. CRL-1573), which is stably transfected with an expression vector pZeoSV (Invitrogen, EMBL accession number L3684~) , which contains the cDNA
for the coding sequence of the human sodium glucose cotransporter 2 (Genbank Acc.
No.I~M 003041 ) (CHO-hSGLT2 or HEK-hSGLT2). These cell lines transport'4C-labelled alpha-methyl-glucopyranoside ('4C-AMG, Amersham) into the interior of the cell in sodium-dependent manner.
The SGLT-2 assay is carried out as follows:
CHO-hSGLT2 cells are cultivated in Hams F12 Medium (BioWhittaker) with 10%
foetal calf serum and 250 Ng/ml zeocin (Invitrogen), and HEK293-hSGLT2 cells are cultivated in DMEM medium with 10% foetal calf serum and 250 Ng/ml zeocin (Invitrogen).
The cells are detached from the culture flasks by washing twice with PBS and subsequently treating with trypsin/EDTA. After the addition of cell culture medium the cells are centrifuged, resuspended in culture medium and counted in a Casy cell counter. Then 40,000 cells per well are seeded into a white, 96-well plate coated with poly-~D-lysine and incubated overnight at 37°C, 5% C02. The cells are washed twice with 250 p1 of assay buffer (Hanks Balanced Salt Solution, 137 mM NaCI, 5.4 mM
KCI, 2.8 mM CaCl2, 1.2 mM MgS04 and 10 mM HEPES (pH7.4), 50 Ng/ml of gentamycin).
250 1I of assay buffer and 5 NI of test compound are then added to each well and the plate is incubated for a further 15 minutes in the incubator. 5 NI of 10% DMSO
are used as the negative control. The reaction is started by adding 5 u1 of '4C-AMG (0.05 NCi) to each well. After 2 hours' incubation at 37°C, 5% C02, the cells are washed again with 250 NI of PBS (20°C) and then lysed by the addition of 25 NI
of 0.1 N NaOH
Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff (5 min. at 37°C). 200 NI of MicroScint20 (Packard) are added to each well and incubation is continued for a further 20 min at 37°C. After this incubation the radioactivity of the '4C-AMG absorbed is measured in a Topcount (Packard) using a '4C scintillation program.
To determine the selectivity with respect to human SGLT1 an analogous test is set up in which the cDNA for hSGLT1 (Genbank Acc. No. NM000343) instead of hSGLT2 cDNA is expressed in CHO-K1 or HEK293 cells.
Alternatively, measurement of the cellular membrane potential for hSGLT1 and hSG~_T2 may also be used for the biological testing of substances. The cell model described earlier may be used for this. For the test, 10,000 cells per well of a black 384-well plate with a transparent base coated with poly-D-lysine are seeded in culture medium and incubated for 16 hours at 37°C, 5% C02. Then the cells are washed twice with glucose-free HBSS buffer (12.67 mol/I CaCl2, 4.93 mmol/I MgCl2, 4.07 mmol:/I MgS04, 4.41 mmol/I KH2P04; pH 7.4) and covered with 20N1 HBSS. After the addition of 20 NI of charging buffer (Membrane Potential Assay Kit Explorer 88126, Molecular Devices GmbH, Ismaning) and 20 NI of the substance to be tested in a suitable concentration, incubation is continued for a further 30 min. at 37°C, 5% C02.
The rneasurement is carried out in the Fluorescent Imaging Plate Reader (Molecular Devices GmbH, Ismaning) at an excitation wavelength of 485 nm and is started by the addition of 20N1 of stimulant buffer (140 mM NaCI and 120 mM glucose). The depolarisation of the cell caused by the glucose-induced influx of Na+ may be measured and quantified as a change in fluorescence.
The compounds of general formula I according to the invention may for example have EC50 values below 1000 nM, particularly below 200 nM, particularly preferably below 50 nM. For example, compound (4) of Example 3 has an EC50 value of about 5 nM
in the S~3LT-2 assay.
In view of their ability to inhibit the SGLT activity, the compounds of general formula I
according to the invention and the corresponding pharmaceutically acceptable salts thereof are theoretically suitable for the treatment and/or preventative treatment of all those conditions or diseases which may be affected by the inhibition of the SGLT
Boer~ringer IngeIheIlT1 CA 02539032 2006-02-24 Case 1/1558 ff _28_ activity, particularly the SGLT-2 activity. Therefore, compounds according to the invention are particularly suitable for the prevention or treatment of diseases, particularly metabolic disorders, or conditions such as type 1 and type 2 diabetes mellitus, complications of diabetes (such as e.g. retinopathy, nephropathy or neuropathies, diabetic foot, ulcers, macroangiopathies), metabolic acidosis or ketosis, reactive hypoglycaemia, hyperinsulinaemia, glucose metabolic disorder, insulin resistance, metabolic syndrome, dyslipidaemias of different origins, atherosclerosis and related diseases, obesity, high blood pressure, chronic heart failure, oedema and hype~ruricaemia. These substances are also suitable for preventing beta-cell degE:neration such as e.g. apoptosis or necrosis of pancreatic beta cells. The substances are also suitable for improving or restoring the functionality of pancreatic cells, and also of increasing the number and size of pancreatic beta cells.
The compounds according to the invention may also be used as diuretics or antihypertensives and are suitable for the prevention and treatment of acute renal failure.
The patient whose illness or condition is to be treated or prevented according to the invention is a mammal, particularly a human being.
In particular, the compounds according to the invention, including the physiologically acceptable salts thereof, are suitable for the prevention or treatment of diabetes, particularly type 1 and type 2 diabetes mellitus, and/or diabetic complications.
The dosage required to achieve the corresponding activity for treatment or prevention usually depends on the compound which is to be administered, the patient, the nature and l~ravity of the illness or condition and the method and frequency of administration and is for the patient's doctor to decide. Expediently, the dosage may be from 1 to 100 mg, preferably 1 to 30 mg, by intravenous route, and 1 to 1000 mg, preferably 1 to 100 mg, by oral route, in each case administered 1 to 4 times a day. For this purpose, the compounds of formula I prepared according to the invention may be formulated, optionally together with other active substances, together with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, Boeh~ringer (ngelhelnl CA 02539032 2006-02-24 Case 1/1558 ff propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, to produce conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.
The compounds according to the invention may also be used in conjunction with other active substances, particularly for the treatment and/or prevention of the diseases and conditions mentioned above. Other active substances which are suitable for such combinations include for example those which potentiate the therapeutic effect of an SGLT antagonist according to the invention with respect to one of the indications mentioned and/or which allow the dosage of an SGLT antagonist according to the invention to be reduced. Therapeutic agents which are suitable for such a combinaton include, for example, antidiabetic agents such as metformin, sulphonylureas (e.g.
glibe~nclamid, tolbutamide, glimepiride), nateglinide, repaglinide, thiazolidinediones (e.g. rosiglitazone, pioglitazone), PPAR-gamma-agonists (e.g. GI 262570) and antagonists, PPAR-gamma/alpha modulators (e.g. KRP 297), alpha-glucosidase inhibitors (e.g. acarbose, voglibose), DPPIV inhibitors (e.g. 1~4F237, MK-431), alpha2-anta~gonists, insulin and insulin analogues, GLP-1 and GLP-1 analogues (e.g.
exendin-4) or amylin. The list also includes inhibitors of protein tyrosinephosphatase 1, substances that affect deregulated glucose production in the liver, such as e.g.
inhibitors of glucose-6-phosphatase, or fructose-1,6-bisphosphatase, glycogen phosphorylase, glucagon receptor antagonists and inhibitors of phosphoenol pyruvate carboxykinase, glycogen synthase kinase or pyruvate dehydrokinase, lipid lowering agents such as for example HMG-CoA-reductase inhibitors (e.g. simvastatin, atorvastatin), fibrates (e.g. bezafibrat, fenofibrat), nicotinic acid and the derivatives thereof, PPAR-alpha agonists, PPAR-delta agonists, ACAT inhibitors (e.g.
avasimibe) or cholesterol absorption inhibitors such as, for example, ezetimibe, bile acid-binding substances such as, for example, cholestyramine, inhibitors of ileac bile acid transport, MDL-increasing compounds such as CETP inhibitors or ABC1 regulators or active substances for treating obesity, such as sibutramin or tetrahydrolipostatin, dexfE~nfluramine, axokine, antagonists of the cannabinoid1 receptor, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists or. f33-agonists such as S13-418790 or AD-9677 and agonists of the 5HT2c receptor.
Boeh~ringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff Moreover, combinations with drugs for influencing high blood pressure, chronic heart failure or atherosclerosis such as e.g. A-II antagonists or ACE inhibitors, ECE
inhibitors, diuretics, f3-blockers, Ca-antagonists, centrally acting antihypertensives, antagonists of the alpha-2-adrenergic receptor, inhibitors of neutral endopeptidase, thrombocyte aggregation inhibitors and others or combinations thereof are suitable.
Examples of angiotensin II receptor antagonists are candesartan cilexetil, potassium losartan, eprosartan mesylate, valsartan, telmisartan, irbesartan, EXP-3174, L-158809, EXP~-3312, olmesartan, medoxomil, tasosartan, KT-3-671, GA-0113, RU-64276, EMD-904:?3, BR-9701, etc.. Angiotensin II receptor antagonists are preferably used for the treai,ment or prevention of high blood pressure and complications of diabetes, often combined with a diuretic such as hydrochlorothiazide.
A combination with uric acid synthesis inhibitors or uricosurics is suitable for the treatment or prevention of gout.
A combination with GABA-receptor antagonists, Na-channel blockers, topiramat, protein-kinase C inhibitors, advanced glycation end product inhibitors or aldose reductase inhibitors may be used for the treatment or prevention of complications of diabetes.
The dosage for the combination partners mentioned above is usefully 1l5 of the lowest dose normally recommended 'up to 1/1 of the normally recommended dose.
Therefore, in another aspect, this invention relates to the use of a compound according to thE: invention or a physiologically acceptable salt of such a compound combined with at least one of the active substances described above as a combination partner, for prep<~ring a pharmaceutical composition which is suitable for the treatment or prevention of diseases or conditions which can be affected by inhibiting the sodium-dependent glucose cotransporter SGLT. These are preferably metabolic diseases, particularly one of the diseases or conditions listed above, most particularly diabetes or diabetic complications.
The use of the compound according to the invention, or a physiologically acceptable salt thereof, in combination with another active substance may take place Boehringer Ingelhelfn CA 02539032 2006-02-24 Case 1/1558 ff simultaneously or at staggered times, but particularly within a short space of time. If they are administered simultaneously, the two active substances are given to the patient together; while if they are used at staggered times the two active substances are given to the patient within a period of less than or equal to 12 hours, but particularly less than or equal to 6 hours.
Consequently, in another aspect, this invention relates to a pharmaceutical composition which comprises a compound according to the invention or a physiologically acceptable salt of such a compound and at least one of the active substances described above as combination partners, optionally together with one or more inert carriers and/or diluents.
Thus, for example, a pharmaceutical composition according to the invention comprises a cornbination of a compound of formula I according to the invention or a physiiologically acceptable salt of such a compound and at least one angiotensin II
rece~>tor antagonist optionally together with one or more inert carriers and/or diluents.
The compound according to the invention, or a physiologically acceptable salt thereof, and the additional active substance to be combined therewith may both be present together in one formulation, for example a tablet or capsule, or separately in two identucal or different formulations, for example as a so-called kit-of-parts.
In the; foregoing and following text, H atoms of hydroxyl groups are not explicitly shown in every case in structural formulae. The Examples that follow are intended to illustrate the present invention without restricting it:
Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff Preparation of the starting compounds:
Example I
~N ~ 1 / \
N~
O
O O O
O ,,,. ,,,, O
O~ O O
1-(2-propyn-1-yl )-3-(2, 3, 4, 6-tetra-O-acetyl-f3-D-glucopyranosyloxy)-4-(4-ethylbenzyl )-5-methyl-1 H-pyrazole 600 mg of 3-(2,3,4,6-tetra-O-acetyl-f3-D-glucopyranosyloxy)-4-(4-ethylbenzyl)-methyl-1H-pyrazole (for synthesis thereof cf. also WO 01/16147, WO 02/53573, WO
02/68439), 390 mg caesium carbonate and 0.091 ml propargyl bromide are stirred in 5 ml of dimethylformamide for 16 hours. A further 195 mg caesium carbonate and 0.046 ml propargyl bromide are added and the mixture is stirred for a further 3 hours at ambient temperature. The reaction mixture is distributed between 25 ml of water and 30 ml of ethyl acetate. The organic phase is separated off, dried and evaporated down.
The residue is purified by chromatography through a silica gel column with a methylene chloride/methanol gradient (99:1 to 95:5).
Yield: 234 mg (36% of theory) Rf value: 0.65 (silica gel; methylene chloride/methanol = 15:1 ) Masa spectrum (ESI+): m/z = 585 [M+H]+
The following compounds are obtained analogously to Example I:
(1) 1-(2-butyn-1-yl)-3-(2,3,4,6-tetra-O-acetyl-f3-D-glucopyranosyloxy)-4-(4-ethylbenzyl)-5-methyl-1 H-pyrazole Boehringer Ingelhell'1'1 CA 02539032 2006-02-24 Case 1/1558 ff N
w O
O O O O
O~''~ '~O
O O
O
Rf value: 0.58 (silica gel, methylene chloride/methanol/cyclohexane = 20:1:2) Mass: spectrum (ESI+): m/z = 599 [M+H]
(2) 1-isopropyl-3-(2,3,4,6-tetra-O-acetyl-f3-D-glucopyranosyloxy)-4-(4-benzyloxybenzyl)-5-methyl-1 H-pyrazole O
N
/
N~
O
~~O O O O
O ,,,. .,,~ O
O O
O
prepared from the compound of Example IV by reaction with isopropyl iodide Rf value: 0.72 (silica gel, cyclohexane/ethyl acetate = 1:1 ) Mass; spectrum (ESI+): m/z = 667 [M+H]
In addition partially deacetylated derivatives of the title compound with Rf values of 0.48, 0.33 and 0.22 are isolated from the reaction mixture (silica gel, cyclohexane/ethyl acetate = 1:1 ).
Boehringer In9elh21f11 CA 02539032 2006-02-24 Case 1/1558 ff Exam- Ip a 11 ~~O
O O
O
Ethyl 2-(4-benzyloxybenzyl)-acetoacetate Prepared by treating ethyl acetoacetate with sodium hydride and subsequently reacting with 4-benzyloxybenzylbromide. The reaction is carried out in tetrahydrofuran.
Rf value: 0.48 (silica gel, cyclohexane/ethyl acetate = 4:1 ) Mass spectrum (ESI+): mlz = 344 [M+NH4]
Example III
O
N- /
N
C) 1,2-dihydro-4-(4-benzyloxybenzyl)-5-methyl-pyrazol-3-one Prepared from the compound of Example II by reacting with hydrazine hydrate in ethanol Rf value: 0.35 (silica gel, methylene chloride/methanol = 9:1 ) Mass spectrum (ESI-): m/z = 293 [M-H]-Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff Exam-ple IV
O
/
O
%~O O O O
O O
O
3-(2,3,4,6-Tetra-O-acetyl-f3-D-glucopyranosyloxy)-4-(4-benzyloxybenzyl)-5-methyl-1 H-pyra~zole 5.1 c~ of 1,2-dihydro-4-(4-benzyloxybenzyl)-5-methyl-pyrazol-3-one, 7.13 g of 2,3,4,6-tetrar0-acetyl-alpha-glucopyranosylbromide and 4.78 g of silver carbonate are stirred for 3. days at 65°C with the exclusion of light. The reaction mixture is filtered through a suction filter, the solid residue is washed with methylene chloride and the filtrate is evaporated down. The crude product is purified by chromatography through a silica gel column with an ethyl acetate/cyclohexane gradient (1:1 to 3:1 ).
Yield: 4.7 g (43% of theory) Rf value: 0.45 (silica gel; ethyl acetate/cyclohexane = 3:1 ) Mass spectrum (ESI+): m/z = 625 [M+H]+
Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff Example V
/ I
O
w O O
0,,,. ~~''O
O
1-isopropyl-3-(13-D-glucopyranosyloxy)-4-(4-benzyloxybenzyl)-5-methyl-1 H-pyrazole is prepared from the partially deacetylated derivatives of the compound of Example I(2) by treatment with lithium hydroxide in tetrahydrofuran/methanol.
Rf value: 0.10 (silica gel; methylene chloride/methanol = 9:1 ) Mass spectrum (ESI+): m/z = 499 [M+H]+
Exam I~~ a VI
O
O
O
1-isopropyl-3-(f3-D-glucopyranosyloxy)-4-(4-hydroxybenzyl)-5-methyl-1 H-pyrazole is prelpared by catalytic hydrogenation of 1-isopropyl-3-(f3-D-glucopyranosyloxy)-4-(4-benzyloxybenzyl)-5-methyl-1 H-pyrazole in methanol in the presence of palladium on activated charcoal (10% Pd) at ambient temperature (approx. 20°C).
Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff Rf value: 0.36 (silica gel; methylene chloride/methanol = 6:1 ) Mass spectrum (ESI+): m/z = 409 [M+H]+
The following compound is obtained analogously to Example VI:
(1) 1-isopropyl-3-(2,3,4,6-tetra-O-acetyl-f3-D-glucopyranosyloxy)-4-(4-hydroxybenzyl)-5-methyl-1 H-pyrazole O
N / I
N
O
~~O O O O
0,,,. .,~~0 O O
O
Rf value: 0.30 (silica gel; methylene chloride/methanol = 9:1 ) Boehringer Ingelhelfl'1 CA 02539032 2006-02-24 Case 1/1558 ff Preparation of the final compounds:
Exarn_~~le 1 ~N ~ 1 N~
O O
O
I~~~O
O
1-(2-propyn-1-yl)-3-(f3-D-glucopyranosyloxy)-4-(4-ethylbenzyl)-5-methyl-1 H-pyrazole A solution of 250 mg of 1-(2-propyn-1-yl)-3-(2,3,4,6-tetra-O-acetyl-f3-D-glucopyranosyloxy)-4-(4-ethylbenzyl)-5-methyl-1H-pyrazole in a mixture of 1 ml of methanol and 2 ml of tetrahydrofuran is cooled in the ice bath and combined with 1.81 ml of a 1 M aqueous lithium hydroxide solution and stirred for 2 hours. The reaction mixture is combined with 5 ml of water and 5 ml of saturated saline solution and extracted with ethyl acetate. The organic phase is separated off, washed with saturated saline solution, dried and evaporated down.
Yield: 167 mg (93% of theory) Rf value: 0.17 (silica gel; methylene chloride/methanol = 9:1 ) Masse spectrum (ESI+): m/z = 417 [M+H]+
The following compound is obtained analogously to Example 1:
(1) 1-(2-butyn-1-yl)-3-(f3-D-glucopyranosyloxy)-4-(4-ethylbenzyl)-5-methyl-1H-pyrazole Boehringer IngeIhelITt CA 02539032 2006-02-24 Case 1/1558 ff N
N \~
O O
O
0,,,. ~~''O
O
R, value: 0.40 (silica gel, methylene chloride/methanol = 9:1 ) Mass spectrum (ESI+): m/z = 431 (M+H]
Exann~le 2 O
'O~O
O
1-(2-propyn-1-yl )-3-(6-O-methoxycarbonyl-f3-D-gl ucopyranosyloxy)-4-(4-ethyl benzyl )-5-methyl-1 H pyrazole 100 rng of 1-(2-propyn-1-yl)-3-(f~-D-glucopyranosyloxy)-4-(4-ethylbenzyl)-5-methyl-1H-pyra~:ole in 0.5 m! 2,4,6-collidine are combined with 0.023 ml of methyl chloroformate in they ice bath and stirred for 6 hours. 3.5 ml 0.1 N hydrochloric acid are added to the reaction mixture and this is then extracted with 10 ml of ethyl acetate. The organic phase is separated off, washed with saturated saline solution and evaporated down.
The residue is taken up in 20 ml of ethyl acetate, washed again with 5 ml 0.1 N
hydrochloric acid and saturated saline solution, dried and evaporated down.
Yield: 85 mg (75% of theory) Rf value: 0.30 (silica gel; methylene chioride/methanol = 9:1 ) Mass spectrum (ESI+): m/z = 475 [M+H]+
Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff The following compound is obtained analogously to Example 2:
(2) 1-(tetrahydropyran-4-yl)-3-(6-O-ethoxycarbonyl-f3-D-glucopyranosyloxy)-4-(4-methoxybenzyl)-5-methyl-1 H-pyrazole O
O~
N / I
N
O
O O
~~O~O
0,,,. ~~''O
O
Rf value: 0.35 (silica gel, methylene chloride/methanol = 9:1 ) Mass spectrum (ESI+): m/z = 537 [M+H]
Example 3 O
..""~N ~ 1 N
O~O~O
O ~~~'~I~~~O
O
1-(( S)-tetrahyd rofuran-2-ylmethyl )-3-(f3-D-glucopyranosyloxy)-4-(4-ethylbenzyl )-5-methyl-1 H-pyrazole 300 mg of 3-(2,3,4,6-Tetra-O-acetyl-f3-D-glucopyranosyloxy)-4-(4-ethylbenzyl)-methyl-1H-pyrazole (for its synthesis cf. also WO 01/16147, WO 02/53573, WO
02/68439), 1808 mg caesium carbonate and 666 mg of (tetrahydrofuran-2-ylmethyl) (S)-p-l:oluenesulphonate are stirred in 5 ml of dimethylforrnamide for 5 hours at 100°C.
Boehringer Ingelheinl CA 02539032 2006-02-24 Case 111558 ff The reaction mixture is evaporated down, and the residue is combined with 0.9 ml of methanol, 1.8 ml of tetrahydrofuran and 1.5 ml of 1 N aqueous lithium hydroxide solution while being cooled in the ice bath. After 2 hours' stirring the reaction mixture is distributed between 20 ml of water and 30 ml of ethyl acetate. The organic phase is waslhed with saturated saline solution, dried and evaporated down. The residue is purified by chromatography through a silica gel column with methylene chloride/methanol (9:1 ).
Yield: 128 mg (50°l0 of theory) Rf v;~lue: 0.40 (silica gei, methylene chlorideJmethanol = 7:1 ) Mas~.s spectrum (ESI+): m/z = 463 [M+H]+
The following compounds are obtained analogously to Example 3:
(3) 'I-((S)-tetrahydrofuran-3-yl)-3-(f3-D-glucopyranosyloxy)-4-(4-ethylbenzyl)-5-methyl-1 H-pyrazole O
N
N
O O
O
O ,,,. ~''' O
O
(Tetrahydrofuran-3-yl) (R)-p-toluenesulphonate may be used as alkylating agent.
Rf value: 0.40 (silica gel, methylene chloridelmethanol = 7:1 ) Mass spectrum (ESI+): m/z = 449 [M+H]
(4) 1-(tetrahydropyran-4-yl)-3-((3-D-glucopyranosyloxy)-4-(4-ethylbenzyl)-5-methyl-1 H-pyrazole Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1!1558 ff O
N
w N~
O O
O
0,,,. .,,,0 O
(Tetrahydropyran-4-yl) p-toluenesulphonate may be used as alkylating agent.
Rf value: 0.40 (silica gel, methylene chloride/methanol = 7:1 ) Mass spectrum (ESI+): m/z = 463 [M+H]
(5) 1-(tetrahydropyran-4-yl)-3-(f3-D-glucopyranosyloxy)-4-(4-methoxybenzyl)-5-methyl-1 H-pyrazole O
N
Ns O i~ O O
0~~~ ~~O
O
The starting material is for example 3-(2,3,4,6-tetra-O-acetyl-f3-D-glucopyranosyloxy)-4-(4-rnethoxybenzyl)-5-methyl-1H pyrazole, as described analogously in WO
or WO 02/53573. (Tetrahydropyran-4-yl) p-toluenesulphonate may be used as alkylating agent.
Rf value: 0.20 (silica gel, methylene chloride/methanol = 9:1 ) Mass spectrum (ESI+): m/z = 465 [M+HJ
Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff Exarnple 4 --~ 0,,,.GO
N / I
w N~
O O
0,,, ..,,0 O
1-isopropyl-3-(f3-D-glucopyranosyloxy)-4-[4-((S)-tetrahydrofuran-3-yloxy)benzyl]-5-methyl-1 H-pyrazole 50 mg 1-isopropyl-3-(f3-D-glucopyranosyloxy)-4-(4-hydroxybenzyl)-5-methyl-1H-pyra~:ole, 33.92 mg of (tetrahydrofuran-3-yl) (R)-p-toluenesulphonate and 45.61 mg of caesium carbonate are stirred in 0.5 ml of dimethylformamide at 50°C
for 16 hours.
The reaction mixture is evaporated down and the residue is purified by chrornatography through a silica gel column.
Yield: 35 mg (60% of theory) Rf value: 0.55 (silica gel, methylene chloride/methanol = 6:1 ) Mass spectrum (ESI+): m/z = 479 [M+H]+
The following compounds are obtained analogously to Example 4:
(6) 1-isopropyl-3-(f3-D-glucopyranosyloxy)-4-[4-((S)-tetrahydrofuran-2-yl-methyloxy)benzyl]-5-methyl-1 H-pyrazole O~;'' O
N / I
N
O O
O ~~~ I~~~O
O
Boehringer Ingeltlelnl CA 02539032 2006-02-24 Case 1/1558 ff Rf value: 0.55 (silica gel, methylene chloride/methanol = 6:1 ) Mass spectrum (ESI+): m/z = 493 [M+H]+
(7) 1-isopropyl-3-(f3-D-glucopyranosyloxy)-4-[4-(tetrahydropyran-4-yloxy)benzyl]-5-methyl-1 H-pyrazole O
N / ~ O
/
N
Oi O O
O''~, ~~''O
O
Rf v,alue: 0.54 (silica gel, methylene chloride/methanol = 6:1 ) Mass spectrum (ESI+): m/z = 493 [M+H]+
R \ R2 N
N \~ Rs RIO O O
R'a0~~~, ~~~~OR'c OR'b (I), wherein the groups R' to R6 and R'a, R'b, R'° are defined hereinafter, including the tautomers, the stereoisomers, the mixtures thereof and the salts thereof. The invention also relates to pharmaceutical compositions containing a compound of formula I
according to the invention as well as the use of a compound according to the invention for preparing a pharmaceutical composition for the treatment of metabolic disorders.
Processes for preparing a pharmaceutical composition and a compound according to the invention are also the subject of this invention.
In the literature, compounds which have an inhibitory effect on the sodium-dependent glucose cotransporter SGLT2 are proposed for the treatment of diseases, particularly diabetes.
Glucopyranosyloxy-pyrazole derivatives and the preparation thereof and their possible activity as SGLT2 inhibitors are known from published International applications WO
02/36602, WO 02/088157, WO 01/16147, WO 02/053573, WO 02/068439, WO
02/068440 and WO 02/098893.
Boehringer Ingeltlelnl CA 02539032 2006-02-24 Case 1/1558 ff Aimi of the invention The aim of the present invention is to find new glucopyranosyloxy-pyrazole derivatives, particularly those which are active with regard to the sodium-dependent glucose cotransporter SGLT, particularly SGLT2. A further aim of the present invention is to discover glucopyranosyloxy-pyrazole derivatives which have an enhanced inhibitory effect on the sodium-dependent glucose cotransporter SGLT2 in vitro and/or in vivo compared with known, structurally similar glucopyranosyloxy-pyrazoles and/or have better pharmacological properties.
A further aim of the present invention is to provide new pharmaceutical compositions which are suitable for the prevention and/or treatment of metabolic disorders, particularly diabetes.
The invention also sets out to provide a process for preparing the compounds aca~rding to the invention.
Other aims of the present invention will become apparent to the skilled man directly from the foregoing and following remarks.
Object of the invention In a first aspect the present invention relates to glucopyranosyloxy-pyrazoles of general formula I
RIO
R
OR'° (I).
wherein B0211f1ng2~ IngelhelfTl CA 02539032 2006-02-24 Cage 1/1558 ff R' denotes C3_6-alkynyl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuranyl-C,_3-alkyl, tetrahydropyranyl-C,_3-alkyl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, or a pyrrolidin-3-yl, piperidin-3-yl or piperidin-4-yl group, while in the latter three groups the nitrogen atom may be substituted by a C~_4-alkyl, formyl, C»-alkyl-carbonyl, C~_4-alkylsulphonyl, cyano, aminocarbonyl, (C~_4-alkyl)-aminocarbonyl, di-(C»-alkyl)-aminocarbonyl or (C~.~-alkyl)-oxycarbonyl group, or if R3 (a) is selected from one of the definitions of the group A; or (b) together with R4 denotes difluoromethylenedioxy; or (c) denotes C3~-cycloalkyl-oxy or C3~-cycloalkylidene-methyl and simultaneously R4 denotes fluorine, chlorine, bromine, C~_3-alkyl, C~_3-alkoxy or a methyl or methoxy group substituted by 1 to 3 fluorine atoms;
then R' may also represent hydrogen, C~_s-alkyl, a C»-alkyl group substituted by 1 to 3 fluorine atoms, a C2~-alkyl group substituted by a hydroxy or C~_3-alkoxy group, or C3~-alkenyl, C3~-cycloalkyl, C~-cycloalkyl-C~_3-alkyl, aryl or aryl-C~_3-alkyl, and R2 denotes C~_4-alkyl, a C~~-alkyl group substituted by 1 to 3 fluorine atoms, or C3_s-cycloalkyl, and R3 denotes hydrogen, fluorine, chlorine, bromine, iodine, C»-alkyl, C2~-alkenyl, C2_6-alkynyl, C3_s-cycloalkyl, C3_6-cycloalkylidenemethyl, C~~-alkoxy, C3_s-cycloalkyl-oxy, C~s-cycloalkyl-C~_3-alkoxy, aryl, aryl-C,_3-alkyl, heteroaryl, heteroaryl-C~_3-alkyl, aryloxy, aryl-C,_3-alkyl-oxy, a methyl or methoxy group substituted by 1 to 3 fluorine atoms, a C2~-alkyl or C2~-alkoxy group substituted by 1 to 5 fluorine atoms, a C~~-alkyl group substituted by a cyano group, a C,_4_alkyl group substituted by a hydroxy or C~_3-alkyloxy group, or cyano, carboxy, C~_3-alkoxycarbonyl, aminocarbonyl, Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff (C~_3-alkylamino)carbonyl, di-(C~_3-alkyl)aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-yl-carbonyl, 4-(C~-alkyl)-piperazin-1-ylcarbonyl, nitro, amino, Ci_3-alkylamino, di-(C~_3-alkyl)amino, (C~_4-alkyl)carbonylamino, C~_4-alkylsulphonylamino, arylsulphonylamino, aryl-C~_3-alkylsulphonylamino, C»-alkylsulphanyl, C~_4-alkylsulphinyl, C~_4-alkylsulphonyl, arylsulphenyl, arylsulphinyl or arylsulphonyl, or has a meaning selected from the group A, and R4 and R5, which may be identical or different, represent hydrogen, fluorine, chlorine, bromine, C~_3-alkyl, C~_3-alko;y, a methyl or methoxy group substituted by 1 to 3 fluorine atoms, or R3 together with R4, if they are bound to adjacent carbon atoms, may also represent a straight-chain C3_5-alkylene, a methylenedioxy or difluoromethylenedioxy bridge, and Rs ~ Rya R'b, R'° independently of one another have a meaning selected from the group hydrogen, (C~_~8-alkyl)carbonyl, (C~_~$-alkyl)oxycarbonyl, arylcarbonyl and aryl-(C~_3-alkyl)-carbonyl, A is selected from the group consisting of tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl-C~_3-alkoxy, tetrahydropyranyl-C~_3-alkoxy, pyrrolidin-3-yloxy, piperidin-3-yloxy, piperidin-4-yloxy group, and pyrrolidin-3-yloxy, piperidin-3-yloxy- and piperidin-4-yloxy, while in the latter three groups the nitrogen atom may be substituted by C~_4-alkyl, formyl, C~_4-alkyl-carbonyl, C,_4-alkylsulphonyl, cyano, aminocarbonyl, (C,_4-alkyl)-aminocarbonyl, di-(C~_4-alkyl)-aminocarbonyl or (C,~-alkyl)-oxycarbonyl, whilE: the aryl groups mentioned in the definition of the above groups are meant to indicate phenyl or naphthyl groups which may be mono- or disubstituted independently Boehringer Ingeltlellll CA 02539032 2006-02-24 Case 1/1558 ff of one another by R,,, while the substituents may be identical or different and R,, denotes a fluorine, chlorine, bromine, iodine, C~_3-alkyl, difluoromethyl, trifluoromethyl, C~_3-alkoxy, difluoromethoxy, trifluoromethoxy or cyano, the Iheteroaryl groups mentioned in the definition of the above-mentioned groups are meant to indicate a pyrrolyl, furanyl, thienyl, pyridyl, indolyl, benzofuranyl, benzothio-phenyl, quinolinyl or isoquinolinyl group, or a pyrrolyl, furanyl, thienyl or pyridyl group, wherein one or two methyne groups are replaced by nitrogen atoms, or an indolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl group, wherein one to three methyne groups are replaced by nitrogen atoms, while the above-mentioned heteroaryl groups may be mono- or disubstituted by R,,, while the substituents may be identical or different and Rh is as hereinbefore defined, while, unless otherwise stated, the above-mentioned alkyl groups may be straight-chain or branched, the tautomers, the stereoisomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof.
The compounds according to the invention of general formula I and the physiologically accE:ptable salts thereof have valuable pharmacological properties, particularly an inhibitory effect on the sodium-dependent glucose cotransporter SGLT, particularly SGLT2. Moreover compounds according to the invention may have an inhibitory effect on the sodium-dependent glucose cotransporter SGLT1. Compared with a possible inhibitory effect on SGLT1 the compounds according to the invention preferably inhibit SGLT2 selectively.
The present invention also relates to the physiologically acceptable salts of the comlpounds according to the invention with inorganic or organic acids.
Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff Therefore, the invention also relates to the use of the compounds according to the invention, including the physiologically acceptable salts, as pharmaceutical compositions.
This invention also relates to pharmaceutical compositions, containing at least one compound according to the invention or a physiologically acceptable salt according to the invention, optionally together with one or more inert carriers and/or diluents.
A further subject of this invention is the use of at least one compound according to the invention or a physiologically acceptable salt of such a compound for preparing a pharmaceutical composition which is suitable for the treatment or prevention of diseases or conditions which can be influenced by inhibiting the sodium-dependent glucose cotransporter SGLT, particularly SGLT2.
This; invention also relates to the use of at least one compound according to the invention for preparing a pharmaceutical composition which is suitable for the treatment of metabolic disorders.
This, invention also relates to the use of at least one compound according to the invention for preparing a pharmaceutical composition for inhibiting the sodium-dep~endent glucose cotransporter SGLT, particularly SGLT2.
The invention further relates to a process for preparing a pharmaceutical composition according to the invention, characterised in that a compound according to the invention is incorporated in one or more inert carriers and/or diluents by a non-chemical method.
The present invention also relates to a process for preparing the compounds according to the invention of general formula I, characterised in that a) in order to prepare compounds of general formula I wherein R' is as here~inbefore defined, but does not denote hydrogen, Boehringer Ingelhelfll CA 02539032 2006-02-24 Case 111558 ff a compound of general formula ~5 RIO O O
R'a0~~~, I~~~OR'c OR'b (II), wherein R2 to R6 and R'a, R'b, R'c are as hereinbefore defined, is reacted with a compound of general formula Z' - R'~ (III), wherein R'~ has the meanings given for R' hereinbefore, but does not denote a hydrogen atom, and Z' denotes a leaving group, or b) in order to prepare compounds of general formula I wherein R3 denotes optionally substituted C~_6-alkoxy, C3_s-cycloalkyl-oxy, C3_5-cycloalkyl-C~_3-alkoxy or a meaning selected from the group A, which is as hereinbefore defined, a compound of general formula Boeriringer Ingelllelnl CA 02539032 2006-02-24 Case 1/1558 ff _g_ RIO
R
OR'° (IV), wherein R', 1~2 and R4 to Rs as well as R'a, R'b, R'° are as hereinbefore defined, is reacted with a compound of general formula Z2 _ Rs, (V), wherein R3~ denotes optionally substituted C~_6-alkoxy, C3~-cycloalkyl-oxy, C~5-cycloalkyl-C~_3-alko:xy or a meaning selected from the group A, which is as hereinbefore defined, and Z2 denotes a leaving group, preferably a halogen atom, for example a chlorine or bromine atom, a sulphonyloxy group, for example a methanesulphonyloxy or p-toluE;nesulphonyloxy group or a hydroxy group, and after step a) or b) has been carried out, if desired a compound of general formula I
thus obtained wherein Rs denotes a hydrogen atom, is converted by acylation into a corrEaponding acyl compound of general formula I, and/or if necessary a protecting group used during the reactions described above is cleaved again and/or if desired a compound of general formula I thus obtained is separated into its stere~oisomers and/or Boehringer Ingelhelfn CA 02539032 2006-02-24 Case 1/1558 ff _g_ a compound of general formula I thus obtained is converted into the salts thereof, partlicularly for pharmaceutical use into the physiologically acceptable salts thereof.
Detailed Description of the invention Unlf;ss otherwise stated the groups, residues and substituents, particularly R' to Rs and R'a, R'b, R'°, are defined as above and hereinafter.
If residues, substituents or groups occur several times in a compound, they may have the Name or different meanings.
The term aryl used above and hereinafter, for example in the groups R', R3, Rs, R'a R'b , R'°, preferably denotes phenyl. According to the general definition and unless otherwise stated, the aryl group, particularly the phenyl group, may be mono-or disubstituted by identical or different groups Rh.
Compounds according to the invention, in a first embodiment of this invention, may be described by general formula I, wherein R' denotes C3_s-alkynyl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuranyl-C~_3-alkyl, tetrahydropyranyl-C~_3-alkyl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, or a pyrrolidin-3-yl, piperidin-3-yl or piperidin-4-yl group, while in the latter three groups the nitrogen atom may be substituted by a C~_4-alkyl, formyl, C~~-alkyl-carbonyl, C~_4-alkylsulphonyl, cyano, aminocarbonyl, (C~_4-alkyl)-aminocarbonyl, di-(C~_4-alkyl)-aminocarbonyl or (C~_4-alkyl)-oxycarbonyl group, and the other groups R2 to Rs and R'a, R'b, R'' are as hereinbefore defined, including the tautomers, the stereoisomers, the mixtures thereof and the salts thereof.
Preferred meanings of the group R' according to this embodiment are 2-propyn-1-yl, 2-butyn-1-yl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, Boef~iringer Ingelhelfll CA 02539032 2006-02-24 Case 1/1558 ff tetrahydrofuranylmethyl and tetrahydropyranylmethyl. Most particularly preferred meanings are 2-propyn-1-yl, 2-butyn-1-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl-and tetrahydrofuran-2-ylmethyl.
Preferred meanings of the group R3 according to this embodiment are hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, tert.-butyl, 2-cyano-2-propyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, cyclopropyl-oxy, cyclnbutyl-oxy, cyclopentyl-oxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethyloxy, tetrahydropyranyl-methyloxy, methylsu!phanyl, 2-methyl-1-propen-1-yl, cyclopropylidenemethyl, ethynyl, phenyl, fluorophenyl, pyridyl and methylthiazolyl. Most particularly preferred meanings are fluorine, chlorine, methyl, ethyl, isopropyl, tert.-butyl, difluoromethyl, trifluoromethyl, cyclnpropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, particularly ethyl.
Preferred meanings of the group R4 according to this first embodiment are hydrogen and fluorine, particularly hydrogen.
Corrrpounds according to the invention in a second embodiment of this invention may be described by general formula I, wherein R' denotes hydrogen, C~_s-alkyl, C~_4-alkyl substituted by 1 to 3 fluorine atoms, C2_4-alkyl substituted by a hydroxy or C~_3-alkoxy group, C3_6-alkenyl, C~6-cycloalkyl, C3~-cycloalkyl-C,_3-alkyl, aryl or aryl-C,_3-alkyl, and R3 is selected from the group A consisting of tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl-Boeh~ringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff C~_3-alkoxy, tetrahydropyranyl-C~_3-alkoxy, pyrrolidin-3-yloxy, piperidin-3-yloxy, piperidin-4-yloxy group, and pyrrolidin-3-yloxy, piperidin-3-yloxy and piperidin-4-yloxy, while in the latter three groups the nitrogen atom is substituted by C~.~-alkyl, formyl, C~~-alkyl-carbonyl, C~_4-alkylsulphonyl, cyano, aminocarbonyl, (C~_4-alkyl)-aminocarbonyl, di-(C~_4-alkyl)-aminocarbonyl or (C~._4-alkyl)-oxycarbonyl, and the other groups, particularly R2 and R4 to R6 and R'a, R'b, R'° are as hereinbefore defined, including the tautomers, the stereoisomers, the mixtures thereof and the salts thereof.
Preferred meanings of the group R' according to this embodiment are C~_s-alkyl, a C,~,-alkyl group substituted by 1 to 3 fluorine atoms, C3~-cycloalkyl and C~-cycloalkyl-C~_3-alkyl, particularly C~_4-alkyl, which may be substituted by 1 to 3 fluorine atoms, most preferably methyl, ethyl, propyl or butyl, most particularly preferably isopropyl.
Preferred meanings of the group R3 according to this embodiment are tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethyloxy and tetrahydropyranylmethyloxy.
Preferred meanings of the group R4 according to this second embodiment are hydrogen and fluorine, particularly hydrogen.
Compounds according to the invention in accordance with a third embodiment of this invention may be described by general formula I, wherein R' denotes hydrogen, C,_s-alkyl, C~_4-alkyl substituted by 1 to 3 fluorine atoms, C2_4-alkyl substituted by a hydroxy or C~_3-alkoxy group, Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff C3_6-alkenyl, C3~-cycloalkyl, C3~-cycloalkyl-C~_3-alkyl, aryl or aryl-C~_3-alkyl, and R3 together with R4, which are bound to adjacent carbon atoms, denotes a difluoromethylenedioxy bridge, and the other groups, particularly R2, R5 and Rs and R'a, R'b, R'° are as hereinbefore defined, including the tautomers, the stereoisomers, the mixtures thE~eof and the salts thereof Preferred meanings of the group R~ according to this embodiment are C~~-alkyl, a C»-alkyl group substituted by 1 to 3 fluorine atoms, C3~-cycloalkyl and C3_s-cycloalkyl-C~_3-alkyl, particularly C~_4-alkyl, which may be substituted by 1 to 3 fluorine atoms, particularly preferably methyl, ethyl, propyl or butyl, most particularly preferably isopiropyl.
Compounds according to the invention in a fourth embodiment of this invention may be described by general formula I, wherein R' denotes hydrogen, C~~-alkyl, C~~-alkyl substituted by 1 to 3 fluorine atoms, C2_4-alkyl substituted by a hydroxy or C~_3-alkoxy group, C3_6-alkenyl, C3_6-cycloalkyl, C3~-cycloalkyl-C~_3-alkyl, aryl or aryl-C~_3-alkyl, and R3 denotes C3~-cycloalkyl-oxy, and Boeh~ringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff R4 denotes fluorine, chlorine, bromine, C~_3-alkyl, C~_3-alkoxy or a methyl or methoxy group substituted by 1 to 3 fluorine atoms, and the other groups, particularly R2, R5 and Rs as well as R'a, R'b, R'°
are as hereinbefore defined, including the tautomers, the stereoisomers, the mixtures thereof and the salts thereof.
Preferred meanings of the group R' according to this embodiment are C»-alkyl, a C»-alkyl group substituted by 1 to 3 fluorine atoms, C3~-cycloalkyl and C3~-cycloalkyl-C~_3-alkyl, particularly C~_4-alkyl, which may to substituted by 1 to 3 fluorine atoms, particularly preferably methyl, ethyl, propyl or butyl, most particularly preferably isopropyl.
Preferred meanings of the group R3 according to this embodiment are cylopropyloxy, cyclnbutyloxy and cyclopentyloxy.
Preferred meanings of the group R4 according to this embodiment are fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxy and trifluoromethoxy, particularly fluorine.
Corrrpounds according to the invention in a fifth embodiment of this invention may be described by general formula I, wherein R' denotes hydrogen, C»-alkyl, C~_4-alkyl substituted by 1 to 3 fluorine atoms, C2_4-alkyl substituted by a hydroxy or C,_3-alkoxy group, C3~-alkenyl, C3_6-cycloalkyl, C3~-cycloalkyl-C~_3-alkyl, aryl or aryl-C~_3-alkyl, and Boehringer Iflgelhelfll CA 02539032 2006-02-24 Case 1/1558 ff R3 denotes C3_s-cycloalkylidene-methyl, and R4 denotes fluorine, chlorine, bromine, C~_3-alkyl, C~_3-alkoxy or a methyl or methoxy group substituted by 1 to 3 fluorine atoms, and the other groups, particularly R2, R5 and R6 and R'a, R'b, R'° are as hereinbefore defined, incluiding the tautomers, the stereoisomers, the mixtures thereof and the salts thereof Preferred meanings of the group R' according to this embodiment are C»-alkyl, C~~-alkyl substituted by 1 to 3 fluorine atoms, C3~-cycloalkyl and C3~-cycloalkyl-C~_3-alkyl, particularly C~~-alkyl, which may be substituted by 1 to 3 fluorine atoms, particularly prefE;rably methyl, ethyl, propyl or butyl, most particularly preferably isopropyl.
A preferred meaning of the group R3 according to this embodiment is cyclopropylidenemethyl.
Preferred meanings of the group R4 according to this embodiment are fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxy and trifluoromethoxy, particularly fluorine.
The following remarks refer to the compounds of formula I, particularly the first, second, third, fourth and fifth embodiments already mentioned above.
If the; group R~ denotes pyrrolidin-3-yl, piperidin-3-yl or piperidin-4-yl, the nitrogen atom is pr~sferably substituted as specified.
According to an alternative to the embodiments described above, other preferred compounds are those wherein the phenyl group which carries the substituents R3, has at least one other substituent R4 and/or R5 which is not hydrogen. According to this alterinative, particularly preferred compounds are those which have a substituent R4 which is fluorine.
Boehringer Ingelheln'1 CA 02539032 2006-02-24 Case 1/1558 ff Preferred meanings of the group R5 are hydrogen and fluorine.
Preferred meanings of the group R2 according to the invention are methyl and trifluoromethyl, particularly methyl.
The group Rs according to the invention preferably denotes hydrogen, (C~_8-alkyl)oxycarbonyl or C~_8-alkylcarbonyl, particularly H or (C~~-alkyl)oxycarbonyl, particularly preferably H, methoxycarbonyl or ethoxycarbonyl.
The substituents R'a, R'b, R'° independently of one another preferably represent hydrogen or (C~_~$-alkyl)carbonyl, particularly hydrogen or (C~_$-alkyl)carbonyl, particularly preferably hydrogen, methylcarbonyl or ethylcarbonyl. Most preferably, R'a, R'b <~nd R'° represent hydrogen.
The compounds of formula I wherein Rs, R'a, R'b and R'° have a meaning according to the invention other than H, for example C~_8-alkylcarbonyl, are preferred as intermediate products for the synthesis of compounds of formula I wherein R'a, R'b and R'' represent hydrogen.
According to the invention compounds of general formula I are preferred wherein R' denotes 2-propyn-1-yl, 2-butyn-1-yl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuranylmethyl or tetrahydropyranylmethyl, or, if R3 (a) is selected from the group consisting of tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethyloxy and tetrahydropyranylmethyloxy, or (b) together with R4 denotes a difluoromethylenedioxy bridge, or, (c) denotes cylopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclopropylidenemethyl and R4 simultaneously denotes fluorine, then R' may also represent isopropyl, and Boehringer Ingelhelftl CA 02539032 2006-02-24 Case 1/1558 ff R2 denotes methyl or trifluoromethyl, R3 denotes hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, tert.-butyl, 2-cyano-2-propyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, cylopropyl-oxy, cyclobutyl-oxy, cyclopentyl-oxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethyloxy, tetrahydropyranylmethyloxy, methylsulphanyl, 2-methyl-1-propen-1-yl, cyclopropylidenemethyl, ethynyl, phenyl, fluorophenyl, pyridyl or methylthiazolyl, and R4 denotes hydrogen or fluorine, or R3 together with R4, if they are bound to adjacent carbon atoms, may also represent a 1,3-propylene, methylenedioxy or difluoromethylenedioxy bridge, and R5 denotes hydrogen and Rs denotes hydrogen, (C~_$-alkyl)oxycarbonyl or C~_$-alkylcarbonyl, the tautomers, the stereoisomers, the mixtures thereof and the salts thereof.
According to the invention compounds of general formula I are particularly preferred wherein R' denotes 2-propyn-1-yl, 2-butyn-1-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl or tetrahydrofuran-2-ylmethyl or, if R3 is selected from the group consisting of tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy and tetrahydrofuranylmethyloxy, then R' may also represent isopropyl, Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff R2 denotes methyl, R3 denotes methyl, ethyl, methoxy, ethoxy, difluoromethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy or tetrahydrofuranylmethyloxy, R4 denotes hydrogen or fluorine RS denotes hydrogen and Rs denotes hydrogen, methoxycarbonyl or ethoxycarbonyl, the i:automers, the stereoisomers, the mixtures thereof and the salts thereof.
According to the invention compounds of general formula I are most particularly preferred, wherein R' denotes tetrahydrofuran-3-yl or tetrahydropyran-4-yl, R2 denotes methyl, R3 denotes methyl, ethyl, methoxy, ethoxy or difluoromethoxy, R4 denotes hydrogen or fluorine, RS denotes hydrogen, R6 denotes hydrogen, methoxycarbonyl or ethoxycarbonyl and R'a, R'b and R'° represent hydrogen, the tautomers, the stereoisomers, the mixtures thereof and the salts thereof.
Parl:icularly preferred compounds of general formula I are selected from the group (a) 1-(2-propyn-1-yl)-3-(f3-D-glucopyranosyloxy)-4-(4-ethylbenzyl)-5-methyl-1 H-pyrazole (b) 1-(2-propyn-1-yl)-3-(6-O-methoxycarbonyl-f3-D-glucopyranosyloxy)-4-(4-ethylbenzyl)-5-methyl-1 H-pyrazole (c) 1-((S)-tetrahydrofuran-3-yl)-3-(f3-D-glucopyranosyloxy)-4-(4-ethylbenzyl)-methyl-1 H-pyrazole Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff (d) 1-(tetrahydropyran-4-yl)-3-(f3-D-glucopyranosyloxy)-4-(4-ethylbenzyl)-5-methyl-1 H-pyrazole, (e) 1-isopropyl-3-(f3-D-glucopyranosyloxy)-4-[4-((S)-tetrahydrofuran-3-yloxy)benzyl]-5-mEahyl-1 H-pyrazole (f) 1-isopropyl-3-(f3-D-glucopyranosyloxy)-4-[4-((R)-tetrahydrofuran-3-yloxy)benzyl]-5-methyl-1 H-pyrazole, (g) 1-(tetrahydropyran-4-yl)-3-(f3-D-glucopyranosyloxy)-4-(4-methoxybenzyl)-5-methyl-1 H-pyrazole, and the derivatives thereof, wherein Rs has a meaning according to the invention other than hydrogen, and in particular Rs denotes ethoxycarbonyl or methoxycarbonyl, including the tautomers, the stereoisomers, the mixtures thereof and the salts thereof.
Some terms used above and hereinafter to describe the compounds according to the invention will now be defined more closely.
The term halogen denotes an atom selected from the group consisting of F, CI, Br and I, particularly F, CI and Br.
The term C~_~-alkyl, wherein n may have a value of 2 to 8, denotes a saturated, branched or unbranched hydrocarbon group with 1 to n C atoms. examples of such groups include methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, tert-pentyl, n-hexyl, iso-hexyl, etc..
The term C,_~-alkylene, wherein n may have a value of 2 to 8, denotes a saturated, branched or unbranched hydrocarbon bridge with 1 to n C atoms. Examples of such groups include methylene (-CH2-), ethylene (-CH2-CH2-), 1-methyl-ethylene (-CH(CH3)-CH2-), 1,1-dimethyl-ethylene (-C(CH3)2-CH2-), n-prop-1,3-ylene (-CH2-Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff CH2-), 1-methylprop-1,3-ylene (-CH(CH3)-CH2-CH2-), 2-methylprop-1,3-ylene (-CH(CH3)-CH2-), etc., as well as the corresponding mirror-symmetrical forms.
The term C2_~ alkenyl, wherein n has a value of 3 to 6, denotes a branched or unbranched hydrocarbon group with 2 to n C atoms and a C=C-double bond.
Examples of such groups include vinyl, 1-propenyl, 2-propenyl, iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, perntenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl etc..
The term C~~ ~-alkynyl, wherein n has a value of 3 to 6, denotes a branched or unbranched hydrocarbon group with 2 to n C atoms and a C--_C triple bond.
Examples of such groups include ethynyl, 1-propynyl, 2-propynyl, iso-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 2-methyl-1-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 3-methyl-2-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl; 5-hexynyl etc.:
The term C~_~-alkoxy or C~_~-alkyloxy denotes a C~_~ alkyl-O group, wherein C1_"-alkyl is as hereinbefore defined. Examples of such groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, iso-pentoxy, neo-pentoxy, tert-pentoxy, n-hexoxy, iso-hexoxy etc..
They term C~_~-alkylcarbonyl denotes a C~_~ alkyl-C(=O) group, wherein C~_~-alkyl is as herninbefore defined. Examples of such groups include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, iso-propylcarbonyl, n-butylcarbonyl, iso-butylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, iso-pentylcarbonyl, neo-pen~tylcarbonyl, tert-pentylcarbonyl, n-hexylcarbonyl, iso-hexylcarbonyl, etc..
The: term C3_~-cycloalkyl denotes a saturated mono-, bi-, tri- or spirocarbocyclic group with 3 to n C atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, bicyclo[3.2.1.]octyl, spiro[4.5]decyl, norpinyl, norbonyl, norcaryl, adamantyl, etc..
Preferably the term C3_~-cycloalkyl denotes saturated monocyclic groups.
Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff The term C5_~-cycloalkenyl denotes a monounsaturated mono-, bi-, tri- or spirocarbocyclic group with 5 to n C atoms. Examples of such groups include cycl~opentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, etc.
The term C~~-cycloalkyloxy denotes a C3_n-cycloalkyl-O group, wherein C~~
cycloalkyl is as hereinbefore defined. Examples of such groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, etc.
The term C3_~-cycloalkylcarbonyl denotes a C~~ cycloalkyl-C(=O) group, wherein C3_n-cycloalkyl is as hereinbefore defined.
The style used above and hereinafter, in which a bond of a substituent in a phenyl group is shown towards the centre of the phenyl ring, denotes, unless otherwise stated, that this substituent may be bound to any free position of the phenyl ring bearing an H atom.
The compounds according to the invention may be obtained using methods of synthesis known in principle. Preferably the compounds are obtained by the following methods according to the invention which are described in more detail hereinafter.
a) In order to prepare compounds of general formula I wherein R' is as her~~inbefore defined, but does not denote a hydrogen atom:
reacting a compound of general formula H
r N
RIO O O
R~aO,~~ ''~,OR~c OR'b (II), wherein Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff R2 t~o R6 as well as R'a, R'b, R'° are as hereinbefore defined, with a compound of general formula Z' - R'~ (III), wherein R'~ has the meanings given for R' hereinbefore, but does not denote a hydrogen atom, and Z' denotes a leaving group, preferably a halogen atom, for example a chlorine or bromine atom, a sulphonyloxy group, for example a methane::ulphonyloxy or p-toluenesulphonyloxy group or a hydroxy group.
The reaction is conveniently carried out in a solvent, such as for example acetonitrile, toluene, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulphoxide or N-methylpyrrolidinone, optionally in the presence of a base, such as for example potassium carbonate, caesium carbonate, sodium hydride or potassium-tert.-butoxide, at temperatures between 20°C and 160°C.
With a compound of general formula III, wherein Z' denotes a hydroxy group, the reaction is carried out in the presence of a dehydrating agent, preferably in the presence of a phosphine and an azodicarboxylic acid derivative such as e.g.
triphenylphosphine/diethyl azodicarboxylate, conveniently in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, dioxane, toluene or ethyleneglycoldiethylether or mixtures thereof at temperatures between -50 and 150°C, but preferably at temperatures between -20 and 80°C.
b) In order to prepare compounds of general formula I wherein R3 denotes optionally substituted C~_s-alkoxy, C3_6-cycloalkyl-oxy, C3_5-cycloalkyl-C~_3-alkoxy or a meaning selected from the group A, which is as hereinbefore defined:
reacting a compound of general formula Boef~iringer Ingelhelfl'1 CA 02539032 2006-02-24 Case 1/1558 ff )H
R' P
RIO O O
R7a0,~~ ''~, OR7c OR'b (IV), wherein R', R2 and R4 to R6 and R'a, R'b, R'c are as hereinbefore defined, with a compound of general formula Z2 _ Rs. (V), wherein R3~ denotes optionally substituted C~_s-alkoxy, C~-cycloalkyl-oxy, C~5-cycloalkyl-C~_3-alkc~xy or a meaning selected from the group A, which is as hereinbefore defined, and Z2 denotes a leaving group, preferably a halogen atom, for example a chlorine or brornine atom, a sulphonyloxy group, for example a methanesulphonyloxy or p-toluenesulphonyloxy group or a hydroxy group.
The reaction is conveniently carried out in a solvent, such as for example acetonitrile, toluene, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulphoxide or N-methylpyrrolidinone, optionally in the presence of a base, such as for example potassium carbonate, caesium carbonate, sodium hydride or potassium-tert.-butoxide, at temperatures between 20°C and 160°C.
With a compound of general formula V, wherein Z2 denotes a hydroxy group, the rea<;tion is carried out in the presence of a dehydrating agent, preferably in the presence of a phosphine and an azodicarboxylic acid derivative such as e.g.
triphenylphosphine/diethyl azodicarboxylate, conveniently in a solvent such as Boehringer Ingelhe11T1 CA 02539032 2006-02-24 Case 1/1558 ff methylene chloride, acetonitrile, tetrahydrofuran, dioxane, toluene or ethyleneglycoldiethylether or mixtures thereof at temperatures between -50 and 150°C, but preferably at temperatures between -20 and 80°C.
If according to the invention a compound of general formula I is obtained wherein R6 denotes a hydrogen atom, this may be converted by acylation, for example by acylation in the presence of a base such as pyridine, collidine, triethylamine or N-ethyl-diisopropylamine, into a compound wherein Rs denotes a (C~_,8-alkyl)carbonyl group, a (C~_,8-alkyl)oxycarbonyl group, an arylcarbonyl group or an aryl-(C~_3-alkyl)-carbonyl group. Suitable acylating agents may be, in particular, the corresponding activated acyl derivatives such as acid chlorides or anhydrides.
In the reactions described hereinbefore, any reactive groups present such as hydroxy, amino, alkylamino or imino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.
For example, a protecting group for a hydroxy group may be a trimethylsilyl, acetyl, benzyl or tetrahydropyranyl group, proi:ecting groups for an amino, alkylamino or imino group may be, for example, a formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group.
Any protecting group used is optionally subsequently cleaved for example by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, acetic acid/water, tetr,ahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali mei:al base such as lithium hydroxide, sodium hydroxide or potassium hydroxide or aprotically, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 12Ci°C, preferably at temperatures between 10 and 100°C.
However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved, for example, hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethyl acetate or Boehringer IngeItleIrT1 CA 02539032 2006-02-24 Case 1/1558 ff glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100°C, but preferably at ambient temperatures between 20 and 60°C, and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar. A
2,4-~dimethoxybenzyl group, however, is preferably cleaved in trifluoroacetic acid in the presence of anisole.
A te:rt.butyl or tert.butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid or by treating with iodotrimethylsilane optionally using a solvent such as methylene chloride, dioxane, methanol or diethylether.
A trifluoroacetyl group is preferably cleaved by treating with an acid such as hydrochloric acid, optionally in the presence of a solvent such as acetic acid at temperatures between 50 and 120°C or by treating with sodium hydroxide solution optionally in the presence of a solvent such as tetrahydrofuran or methanol at temperatures between 0 and 50°C.
Moreover, the compounds of general formula I obtained may be resolved into their enantiomers and/or diastereomers, as mentioned hereinbefore. Thus, for example, cisl'trans mixtures may be resolved into their cis and trans isomers, and compounds with at least one optically active carbon atom may be separated into their enantiomers.
Thus, for example, the cisltrans mixtures may be resolved by chromatography into the cis and trans isomers thereof, the compounds of general formula I obtained which occur as racemates may be separated by methods known per se (cf. Allinger N.
L. and EIiE;I E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971 ) into their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.
ThE: enantiomers are preferably separated by column separation on chiral phases or by irecrystallisation from an optically active solvent or by reacting with an optically Boehringer IflgelhelfTl CA 02539032 2006-02-24 Case 1/1558 ff active substance which forms salts or derivatives such as e.g. esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Optically active acids in common use are e.g. the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. An optically active alcohol may be for example (+) or (-menthol and an optically active acyl group in amides, for example, may be a (+~or (-)-menthyloxycarbonyl.
Furthermore, the compounds of formula I may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts with inorcaanic or organic acids. Acids which may be used for this purpose include for exarnple hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or malefic acid.
Morf:over, the compounds obtained may be converted into mixtures, for example 1:1 or 1:2 mixtures with amino acids, particularly with alpha-amino acids such as proline or phenylalanine, which may have particularly favourable properties such as a high crystallinity.
The .compounds of general formulae I I to V used as starting materials are partly known from the literature or may be obtained by methods known from the literature {see Examples I to VI), optionally with the additional inclusion of protecting groups.
The compounds according to the invention may advantageously also be obtained by the methods described in the following examples, which may also be combined with methods known to the skilled man from the literature, for example, particularly the methods described in WO 02/36602, WO 02/088157, WO 01/16147, WO 02/053573, WO 021068439, WO 02/068440 and WO 02/098893.
Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff As already mentioned, the compounds of general formula I according to the invention and the physiologically acceptable salts thereof have valuable pharmacological properties, particularly an inhibitory effect on the sodium-dependent glucose cotransporter SGLT, preferably SGLT2.
The biological properties of the new compounds may be investigated as follows:
The ability of the substances to inhibit the SGLT-2 activity may be demonstrated in a test set-up in which a CHO-K1 cell line (ATCC No. CCL 61 ) or alternatively an cell line (ATCC No. CRL-1573), which is stably transfected with an expression vector pZeoSV (Invitrogen, EMBL accession number L3684~) , which contains the cDNA
for the coding sequence of the human sodium glucose cotransporter 2 (Genbank Acc.
No.I~M 003041 ) (CHO-hSGLT2 or HEK-hSGLT2). These cell lines transport'4C-labelled alpha-methyl-glucopyranoside ('4C-AMG, Amersham) into the interior of the cell in sodium-dependent manner.
The SGLT-2 assay is carried out as follows:
CHO-hSGLT2 cells are cultivated in Hams F12 Medium (BioWhittaker) with 10%
foetal calf serum and 250 Ng/ml zeocin (Invitrogen), and HEK293-hSGLT2 cells are cultivated in DMEM medium with 10% foetal calf serum and 250 Ng/ml zeocin (Invitrogen).
The cells are detached from the culture flasks by washing twice with PBS and subsequently treating with trypsin/EDTA. After the addition of cell culture medium the cells are centrifuged, resuspended in culture medium and counted in a Casy cell counter. Then 40,000 cells per well are seeded into a white, 96-well plate coated with poly-~D-lysine and incubated overnight at 37°C, 5% C02. The cells are washed twice with 250 p1 of assay buffer (Hanks Balanced Salt Solution, 137 mM NaCI, 5.4 mM
KCI, 2.8 mM CaCl2, 1.2 mM MgS04 and 10 mM HEPES (pH7.4), 50 Ng/ml of gentamycin).
250 1I of assay buffer and 5 NI of test compound are then added to each well and the plate is incubated for a further 15 minutes in the incubator. 5 NI of 10% DMSO
are used as the negative control. The reaction is started by adding 5 u1 of '4C-AMG (0.05 NCi) to each well. After 2 hours' incubation at 37°C, 5% C02, the cells are washed again with 250 NI of PBS (20°C) and then lysed by the addition of 25 NI
of 0.1 N NaOH
Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff (5 min. at 37°C). 200 NI of MicroScint20 (Packard) are added to each well and incubation is continued for a further 20 min at 37°C. After this incubation the radioactivity of the '4C-AMG absorbed is measured in a Topcount (Packard) using a '4C scintillation program.
To determine the selectivity with respect to human SGLT1 an analogous test is set up in which the cDNA for hSGLT1 (Genbank Acc. No. NM000343) instead of hSGLT2 cDNA is expressed in CHO-K1 or HEK293 cells.
Alternatively, measurement of the cellular membrane potential for hSGLT1 and hSG~_T2 may also be used for the biological testing of substances. The cell model described earlier may be used for this. For the test, 10,000 cells per well of a black 384-well plate with a transparent base coated with poly-D-lysine are seeded in culture medium and incubated for 16 hours at 37°C, 5% C02. Then the cells are washed twice with glucose-free HBSS buffer (12.67 mol/I CaCl2, 4.93 mmol/I MgCl2, 4.07 mmol:/I MgS04, 4.41 mmol/I KH2P04; pH 7.4) and covered with 20N1 HBSS. After the addition of 20 NI of charging buffer (Membrane Potential Assay Kit Explorer 88126, Molecular Devices GmbH, Ismaning) and 20 NI of the substance to be tested in a suitable concentration, incubation is continued for a further 30 min. at 37°C, 5% C02.
The rneasurement is carried out in the Fluorescent Imaging Plate Reader (Molecular Devices GmbH, Ismaning) at an excitation wavelength of 485 nm and is started by the addition of 20N1 of stimulant buffer (140 mM NaCI and 120 mM glucose). The depolarisation of the cell caused by the glucose-induced influx of Na+ may be measured and quantified as a change in fluorescence.
The compounds of general formula I according to the invention may for example have EC50 values below 1000 nM, particularly below 200 nM, particularly preferably below 50 nM. For example, compound (4) of Example 3 has an EC50 value of about 5 nM
in the S~3LT-2 assay.
In view of their ability to inhibit the SGLT activity, the compounds of general formula I
according to the invention and the corresponding pharmaceutically acceptable salts thereof are theoretically suitable for the treatment and/or preventative treatment of all those conditions or diseases which may be affected by the inhibition of the SGLT
Boer~ringer IngeIheIlT1 CA 02539032 2006-02-24 Case 1/1558 ff _28_ activity, particularly the SGLT-2 activity. Therefore, compounds according to the invention are particularly suitable for the prevention or treatment of diseases, particularly metabolic disorders, or conditions such as type 1 and type 2 diabetes mellitus, complications of diabetes (such as e.g. retinopathy, nephropathy or neuropathies, diabetic foot, ulcers, macroangiopathies), metabolic acidosis or ketosis, reactive hypoglycaemia, hyperinsulinaemia, glucose metabolic disorder, insulin resistance, metabolic syndrome, dyslipidaemias of different origins, atherosclerosis and related diseases, obesity, high blood pressure, chronic heart failure, oedema and hype~ruricaemia. These substances are also suitable for preventing beta-cell degE:neration such as e.g. apoptosis or necrosis of pancreatic beta cells. The substances are also suitable for improving or restoring the functionality of pancreatic cells, and also of increasing the number and size of pancreatic beta cells.
The compounds according to the invention may also be used as diuretics or antihypertensives and are suitable for the prevention and treatment of acute renal failure.
The patient whose illness or condition is to be treated or prevented according to the invention is a mammal, particularly a human being.
In particular, the compounds according to the invention, including the physiologically acceptable salts thereof, are suitable for the prevention or treatment of diabetes, particularly type 1 and type 2 diabetes mellitus, and/or diabetic complications.
The dosage required to achieve the corresponding activity for treatment or prevention usually depends on the compound which is to be administered, the patient, the nature and l~ravity of the illness or condition and the method and frequency of administration and is for the patient's doctor to decide. Expediently, the dosage may be from 1 to 100 mg, preferably 1 to 30 mg, by intravenous route, and 1 to 1000 mg, preferably 1 to 100 mg, by oral route, in each case administered 1 to 4 times a day. For this purpose, the compounds of formula I prepared according to the invention may be formulated, optionally together with other active substances, together with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, Boeh~ringer (ngelhelnl CA 02539032 2006-02-24 Case 1/1558 ff propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, to produce conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.
The compounds according to the invention may also be used in conjunction with other active substances, particularly for the treatment and/or prevention of the diseases and conditions mentioned above. Other active substances which are suitable for such combinations include for example those which potentiate the therapeutic effect of an SGLT antagonist according to the invention with respect to one of the indications mentioned and/or which allow the dosage of an SGLT antagonist according to the invention to be reduced. Therapeutic agents which are suitable for such a combinaton include, for example, antidiabetic agents such as metformin, sulphonylureas (e.g.
glibe~nclamid, tolbutamide, glimepiride), nateglinide, repaglinide, thiazolidinediones (e.g. rosiglitazone, pioglitazone), PPAR-gamma-agonists (e.g. GI 262570) and antagonists, PPAR-gamma/alpha modulators (e.g. KRP 297), alpha-glucosidase inhibitors (e.g. acarbose, voglibose), DPPIV inhibitors (e.g. 1~4F237, MK-431), alpha2-anta~gonists, insulin and insulin analogues, GLP-1 and GLP-1 analogues (e.g.
exendin-4) or amylin. The list also includes inhibitors of protein tyrosinephosphatase 1, substances that affect deregulated glucose production in the liver, such as e.g.
inhibitors of glucose-6-phosphatase, or fructose-1,6-bisphosphatase, glycogen phosphorylase, glucagon receptor antagonists and inhibitors of phosphoenol pyruvate carboxykinase, glycogen synthase kinase or pyruvate dehydrokinase, lipid lowering agents such as for example HMG-CoA-reductase inhibitors (e.g. simvastatin, atorvastatin), fibrates (e.g. bezafibrat, fenofibrat), nicotinic acid and the derivatives thereof, PPAR-alpha agonists, PPAR-delta agonists, ACAT inhibitors (e.g.
avasimibe) or cholesterol absorption inhibitors such as, for example, ezetimibe, bile acid-binding substances such as, for example, cholestyramine, inhibitors of ileac bile acid transport, MDL-increasing compounds such as CETP inhibitors or ABC1 regulators or active substances for treating obesity, such as sibutramin or tetrahydrolipostatin, dexfE~nfluramine, axokine, antagonists of the cannabinoid1 receptor, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists or. f33-agonists such as S13-418790 or AD-9677 and agonists of the 5HT2c receptor.
Boeh~ringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff Moreover, combinations with drugs for influencing high blood pressure, chronic heart failure or atherosclerosis such as e.g. A-II antagonists or ACE inhibitors, ECE
inhibitors, diuretics, f3-blockers, Ca-antagonists, centrally acting antihypertensives, antagonists of the alpha-2-adrenergic receptor, inhibitors of neutral endopeptidase, thrombocyte aggregation inhibitors and others or combinations thereof are suitable.
Examples of angiotensin II receptor antagonists are candesartan cilexetil, potassium losartan, eprosartan mesylate, valsartan, telmisartan, irbesartan, EXP-3174, L-158809, EXP~-3312, olmesartan, medoxomil, tasosartan, KT-3-671, GA-0113, RU-64276, EMD-904:?3, BR-9701, etc.. Angiotensin II receptor antagonists are preferably used for the treai,ment or prevention of high blood pressure and complications of diabetes, often combined with a diuretic such as hydrochlorothiazide.
A combination with uric acid synthesis inhibitors or uricosurics is suitable for the treatment or prevention of gout.
A combination with GABA-receptor antagonists, Na-channel blockers, topiramat, protein-kinase C inhibitors, advanced glycation end product inhibitors or aldose reductase inhibitors may be used for the treatment or prevention of complications of diabetes.
The dosage for the combination partners mentioned above is usefully 1l5 of the lowest dose normally recommended 'up to 1/1 of the normally recommended dose.
Therefore, in another aspect, this invention relates to the use of a compound according to thE: invention or a physiologically acceptable salt of such a compound combined with at least one of the active substances described above as a combination partner, for prep<~ring a pharmaceutical composition which is suitable for the treatment or prevention of diseases or conditions which can be affected by inhibiting the sodium-dependent glucose cotransporter SGLT. These are preferably metabolic diseases, particularly one of the diseases or conditions listed above, most particularly diabetes or diabetic complications.
The use of the compound according to the invention, or a physiologically acceptable salt thereof, in combination with another active substance may take place Boehringer Ingelhelfn CA 02539032 2006-02-24 Case 1/1558 ff simultaneously or at staggered times, but particularly within a short space of time. If they are administered simultaneously, the two active substances are given to the patient together; while if they are used at staggered times the two active substances are given to the patient within a period of less than or equal to 12 hours, but particularly less than or equal to 6 hours.
Consequently, in another aspect, this invention relates to a pharmaceutical composition which comprises a compound according to the invention or a physiologically acceptable salt of such a compound and at least one of the active substances described above as combination partners, optionally together with one or more inert carriers and/or diluents.
Thus, for example, a pharmaceutical composition according to the invention comprises a cornbination of a compound of formula I according to the invention or a physiiologically acceptable salt of such a compound and at least one angiotensin II
rece~>tor antagonist optionally together with one or more inert carriers and/or diluents.
The compound according to the invention, or a physiologically acceptable salt thereof, and the additional active substance to be combined therewith may both be present together in one formulation, for example a tablet or capsule, or separately in two identucal or different formulations, for example as a so-called kit-of-parts.
In the; foregoing and following text, H atoms of hydroxyl groups are not explicitly shown in every case in structural formulae. The Examples that follow are intended to illustrate the present invention without restricting it:
Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff Preparation of the starting compounds:
Example I
~N ~ 1 / \
N~
O
O O O
O ,,,. ,,,, O
O~ O O
1-(2-propyn-1-yl )-3-(2, 3, 4, 6-tetra-O-acetyl-f3-D-glucopyranosyloxy)-4-(4-ethylbenzyl )-5-methyl-1 H-pyrazole 600 mg of 3-(2,3,4,6-tetra-O-acetyl-f3-D-glucopyranosyloxy)-4-(4-ethylbenzyl)-methyl-1H-pyrazole (for synthesis thereof cf. also WO 01/16147, WO 02/53573, WO
02/68439), 390 mg caesium carbonate and 0.091 ml propargyl bromide are stirred in 5 ml of dimethylformamide for 16 hours. A further 195 mg caesium carbonate and 0.046 ml propargyl bromide are added and the mixture is stirred for a further 3 hours at ambient temperature. The reaction mixture is distributed between 25 ml of water and 30 ml of ethyl acetate. The organic phase is separated off, dried and evaporated down.
The residue is purified by chromatography through a silica gel column with a methylene chloride/methanol gradient (99:1 to 95:5).
Yield: 234 mg (36% of theory) Rf value: 0.65 (silica gel; methylene chloride/methanol = 15:1 ) Masa spectrum (ESI+): m/z = 585 [M+H]+
The following compounds are obtained analogously to Example I:
(1) 1-(2-butyn-1-yl)-3-(2,3,4,6-tetra-O-acetyl-f3-D-glucopyranosyloxy)-4-(4-ethylbenzyl)-5-methyl-1 H-pyrazole Boehringer Ingelhell'1'1 CA 02539032 2006-02-24 Case 1/1558 ff N
w O
O O O O
O~''~ '~O
O O
O
Rf value: 0.58 (silica gel, methylene chloride/methanol/cyclohexane = 20:1:2) Mass: spectrum (ESI+): m/z = 599 [M+H]
(2) 1-isopropyl-3-(2,3,4,6-tetra-O-acetyl-f3-D-glucopyranosyloxy)-4-(4-benzyloxybenzyl)-5-methyl-1 H-pyrazole O
N
/
N~
O
~~O O O O
O ,,,. .,,~ O
O O
O
prepared from the compound of Example IV by reaction with isopropyl iodide Rf value: 0.72 (silica gel, cyclohexane/ethyl acetate = 1:1 ) Mass; spectrum (ESI+): m/z = 667 [M+H]
In addition partially deacetylated derivatives of the title compound with Rf values of 0.48, 0.33 and 0.22 are isolated from the reaction mixture (silica gel, cyclohexane/ethyl acetate = 1:1 ).
Boehringer In9elh21f11 CA 02539032 2006-02-24 Case 1/1558 ff Exam- Ip a 11 ~~O
O O
O
Ethyl 2-(4-benzyloxybenzyl)-acetoacetate Prepared by treating ethyl acetoacetate with sodium hydride and subsequently reacting with 4-benzyloxybenzylbromide. The reaction is carried out in tetrahydrofuran.
Rf value: 0.48 (silica gel, cyclohexane/ethyl acetate = 4:1 ) Mass spectrum (ESI+): mlz = 344 [M+NH4]
Example III
O
N- /
N
C) 1,2-dihydro-4-(4-benzyloxybenzyl)-5-methyl-pyrazol-3-one Prepared from the compound of Example II by reacting with hydrazine hydrate in ethanol Rf value: 0.35 (silica gel, methylene chloride/methanol = 9:1 ) Mass spectrum (ESI-): m/z = 293 [M-H]-Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff Exam-ple IV
O
/
O
%~O O O O
O O
O
3-(2,3,4,6-Tetra-O-acetyl-f3-D-glucopyranosyloxy)-4-(4-benzyloxybenzyl)-5-methyl-1 H-pyra~zole 5.1 c~ of 1,2-dihydro-4-(4-benzyloxybenzyl)-5-methyl-pyrazol-3-one, 7.13 g of 2,3,4,6-tetrar0-acetyl-alpha-glucopyranosylbromide and 4.78 g of silver carbonate are stirred for 3. days at 65°C with the exclusion of light. The reaction mixture is filtered through a suction filter, the solid residue is washed with methylene chloride and the filtrate is evaporated down. The crude product is purified by chromatography through a silica gel column with an ethyl acetate/cyclohexane gradient (1:1 to 3:1 ).
Yield: 4.7 g (43% of theory) Rf value: 0.45 (silica gel; ethyl acetate/cyclohexane = 3:1 ) Mass spectrum (ESI+): m/z = 625 [M+H]+
Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff Example V
/ I
O
w O O
0,,,. ~~''O
O
1-isopropyl-3-(13-D-glucopyranosyloxy)-4-(4-benzyloxybenzyl)-5-methyl-1 H-pyrazole is prepared from the partially deacetylated derivatives of the compound of Example I(2) by treatment with lithium hydroxide in tetrahydrofuran/methanol.
Rf value: 0.10 (silica gel; methylene chloride/methanol = 9:1 ) Mass spectrum (ESI+): m/z = 499 [M+H]+
Exam I~~ a VI
O
O
O
1-isopropyl-3-(f3-D-glucopyranosyloxy)-4-(4-hydroxybenzyl)-5-methyl-1 H-pyrazole is prelpared by catalytic hydrogenation of 1-isopropyl-3-(f3-D-glucopyranosyloxy)-4-(4-benzyloxybenzyl)-5-methyl-1 H-pyrazole in methanol in the presence of palladium on activated charcoal (10% Pd) at ambient temperature (approx. 20°C).
Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff Rf value: 0.36 (silica gel; methylene chloride/methanol = 6:1 ) Mass spectrum (ESI+): m/z = 409 [M+H]+
The following compound is obtained analogously to Example VI:
(1) 1-isopropyl-3-(2,3,4,6-tetra-O-acetyl-f3-D-glucopyranosyloxy)-4-(4-hydroxybenzyl)-5-methyl-1 H-pyrazole O
N / I
N
O
~~O O O O
0,,,. .,~~0 O O
O
Rf value: 0.30 (silica gel; methylene chloride/methanol = 9:1 ) Boehringer Ingelhelfl'1 CA 02539032 2006-02-24 Case 1/1558 ff Preparation of the final compounds:
Exarn_~~le 1 ~N ~ 1 N~
O O
O
I~~~O
O
1-(2-propyn-1-yl)-3-(f3-D-glucopyranosyloxy)-4-(4-ethylbenzyl)-5-methyl-1 H-pyrazole A solution of 250 mg of 1-(2-propyn-1-yl)-3-(2,3,4,6-tetra-O-acetyl-f3-D-glucopyranosyloxy)-4-(4-ethylbenzyl)-5-methyl-1H-pyrazole in a mixture of 1 ml of methanol and 2 ml of tetrahydrofuran is cooled in the ice bath and combined with 1.81 ml of a 1 M aqueous lithium hydroxide solution and stirred for 2 hours. The reaction mixture is combined with 5 ml of water and 5 ml of saturated saline solution and extracted with ethyl acetate. The organic phase is separated off, washed with saturated saline solution, dried and evaporated down.
Yield: 167 mg (93% of theory) Rf value: 0.17 (silica gel; methylene chloride/methanol = 9:1 ) Masse spectrum (ESI+): m/z = 417 [M+H]+
The following compound is obtained analogously to Example 1:
(1) 1-(2-butyn-1-yl)-3-(f3-D-glucopyranosyloxy)-4-(4-ethylbenzyl)-5-methyl-1H-pyrazole Boehringer IngeIhelITt CA 02539032 2006-02-24 Case 1/1558 ff N
N \~
O O
O
0,,,. ~~''O
O
R, value: 0.40 (silica gel, methylene chloride/methanol = 9:1 ) Mass spectrum (ESI+): m/z = 431 (M+H]
Exann~le 2 O
'O~O
O
1-(2-propyn-1-yl )-3-(6-O-methoxycarbonyl-f3-D-gl ucopyranosyloxy)-4-(4-ethyl benzyl )-5-methyl-1 H pyrazole 100 rng of 1-(2-propyn-1-yl)-3-(f~-D-glucopyranosyloxy)-4-(4-ethylbenzyl)-5-methyl-1H-pyra~:ole in 0.5 m! 2,4,6-collidine are combined with 0.023 ml of methyl chloroformate in they ice bath and stirred for 6 hours. 3.5 ml 0.1 N hydrochloric acid are added to the reaction mixture and this is then extracted with 10 ml of ethyl acetate. The organic phase is separated off, washed with saturated saline solution and evaporated down.
The residue is taken up in 20 ml of ethyl acetate, washed again with 5 ml 0.1 N
hydrochloric acid and saturated saline solution, dried and evaporated down.
Yield: 85 mg (75% of theory) Rf value: 0.30 (silica gel; methylene chioride/methanol = 9:1 ) Mass spectrum (ESI+): m/z = 475 [M+H]+
Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff The following compound is obtained analogously to Example 2:
(2) 1-(tetrahydropyran-4-yl)-3-(6-O-ethoxycarbonyl-f3-D-glucopyranosyloxy)-4-(4-methoxybenzyl)-5-methyl-1 H-pyrazole O
O~
N / I
N
O
O O
~~O~O
0,,,. ~~''O
O
Rf value: 0.35 (silica gel, methylene chloride/methanol = 9:1 ) Mass spectrum (ESI+): m/z = 537 [M+H]
Example 3 O
..""~N ~ 1 N
O~O~O
O ~~~'~I~~~O
O
1-(( S)-tetrahyd rofuran-2-ylmethyl )-3-(f3-D-glucopyranosyloxy)-4-(4-ethylbenzyl )-5-methyl-1 H-pyrazole 300 mg of 3-(2,3,4,6-Tetra-O-acetyl-f3-D-glucopyranosyloxy)-4-(4-ethylbenzyl)-methyl-1H-pyrazole (for its synthesis cf. also WO 01/16147, WO 02/53573, WO
02/68439), 1808 mg caesium carbonate and 666 mg of (tetrahydrofuran-2-ylmethyl) (S)-p-l:oluenesulphonate are stirred in 5 ml of dimethylforrnamide for 5 hours at 100°C.
Boehringer Ingelheinl CA 02539032 2006-02-24 Case 111558 ff The reaction mixture is evaporated down, and the residue is combined with 0.9 ml of methanol, 1.8 ml of tetrahydrofuran and 1.5 ml of 1 N aqueous lithium hydroxide solution while being cooled in the ice bath. After 2 hours' stirring the reaction mixture is distributed between 20 ml of water and 30 ml of ethyl acetate. The organic phase is waslhed with saturated saline solution, dried and evaporated down. The residue is purified by chromatography through a silica gel column with methylene chloride/methanol (9:1 ).
Yield: 128 mg (50°l0 of theory) Rf v;~lue: 0.40 (silica gei, methylene chlorideJmethanol = 7:1 ) Mas~.s spectrum (ESI+): m/z = 463 [M+H]+
The following compounds are obtained analogously to Example 3:
(3) 'I-((S)-tetrahydrofuran-3-yl)-3-(f3-D-glucopyranosyloxy)-4-(4-ethylbenzyl)-5-methyl-1 H-pyrazole O
N
N
O O
O
O ,,,. ~''' O
O
(Tetrahydrofuran-3-yl) (R)-p-toluenesulphonate may be used as alkylating agent.
Rf value: 0.40 (silica gel, methylene chloridelmethanol = 7:1 ) Mass spectrum (ESI+): m/z = 449 [M+H]
(4) 1-(tetrahydropyran-4-yl)-3-((3-D-glucopyranosyloxy)-4-(4-ethylbenzyl)-5-methyl-1 H-pyrazole Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1!1558 ff O
N
w N~
O O
O
0,,,. .,,,0 O
(Tetrahydropyran-4-yl) p-toluenesulphonate may be used as alkylating agent.
Rf value: 0.40 (silica gel, methylene chloride/methanol = 7:1 ) Mass spectrum (ESI+): m/z = 463 [M+H]
(5) 1-(tetrahydropyran-4-yl)-3-(f3-D-glucopyranosyloxy)-4-(4-methoxybenzyl)-5-methyl-1 H-pyrazole O
N
Ns O i~ O O
0~~~ ~~O
O
The starting material is for example 3-(2,3,4,6-tetra-O-acetyl-f3-D-glucopyranosyloxy)-4-(4-rnethoxybenzyl)-5-methyl-1H pyrazole, as described analogously in WO
or WO 02/53573. (Tetrahydropyran-4-yl) p-toluenesulphonate may be used as alkylating agent.
Rf value: 0.20 (silica gel, methylene chloride/methanol = 9:1 ) Mass spectrum (ESI+): m/z = 465 [M+HJ
Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff Exarnple 4 --~ 0,,,.GO
N / I
w N~
O O
0,,, ..,,0 O
1-isopropyl-3-(f3-D-glucopyranosyloxy)-4-[4-((S)-tetrahydrofuran-3-yloxy)benzyl]-5-methyl-1 H-pyrazole 50 mg 1-isopropyl-3-(f3-D-glucopyranosyloxy)-4-(4-hydroxybenzyl)-5-methyl-1H-pyra~:ole, 33.92 mg of (tetrahydrofuran-3-yl) (R)-p-toluenesulphonate and 45.61 mg of caesium carbonate are stirred in 0.5 ml of dimethylformamide at 50°C
for 16 hours.
The reaction mixture is evaporated down and the residue is purified by chrornatography through a silica gel column.
Yield: 35 mg (60% of theory) Rf value: 0.55 (silica gel, methylene chloride/methanol = 6:1 ) Mass spectrum (ESI+): m/z = 479 [M+H]+
The following compounds are obtained analogously to Example 4:
(6) 1-isopropyl-3-(f3-D-glucopyranosyloxy)-4-[4-((S)-tetrahydrofuran-2-yl-methyloxy)benzyl]-5-methyl-1 H-pyrazole O~;'' O
N / I
N
O O
O ~~~ I~~~O
O
Boehringer Ingeltlelnl CA 02539032 2006-02-24 Case 1/1558 ff Rf value: 0.55 (silica gel, methylene chloride/methanol = 6:1 ) Mass spectrum (ESI+): m/z = 493 [M+H]+
(7) 1-isopropyl-3-(f3-D-glucopyranosyloxy)-4-[4-(tetrahydropyran-4-yloxy)benzyl]-5-methyl-1 H-pyrazole O
N / ~ O
/
N
Oi O O
O''~, ~~''O
O
Rf v,alue: 0.54 (silica gel, methylene chloride/methanol = 6:1 ) Mass spectrum (ESI+): m/z = 493 [M+H]+
(8) '1-isopropyl-3-(f3-D-glucopyranosyloxy)-4-[4-((R)-tetrahydrofuran-3-yloxy)benzyl]-5-methyl-1 H-pyrazole O O
N
N
O O
O''~. ~~''O
O
Prepared by alkylation of the compound of Example VI(1 ) and subsequent hydrolysis of the acetyl groups analogously to Example V
Mass spectrum (ESI+): m/z = 479 [M+H]+
Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff The following compounds are also prepared analogously to the above-mentioned Examples and other methods known from the literature:
(10) HO
(11) HO
N
(12) N, HO
HO~~1,~.~~~OH
OH
O~~, ~N ~ I
(13) HO
HO~~~, ~~~OH
OH
O
~N
( 14) HO
HO~~~~ ~~~OH
OH
Boehrin~ger 111gelhelfll CA 02539032 2006-02-24 Case 111558 ff n~
(15) o'~
(16) ~o~o o~
(17) ~o~o ( 18) ri HO~~~~ ~~~OH
OH
(19) ~o Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 111b58 ff (20) o~
(21) N \
N~ -O
O O
~O~O
HO~~~, ~~~OH
OH
n~
(22) ~o~o (23) o~o OH
O
\~/ /
(24) N~
O O
HO
HO~~~' ~~~OH
OH
Case 1!1558 ff $Oehflfl9ef Ifl9elhelfll CA 02539032 2006-02-24 (25) HO
(26) HO
OH
(27) (28) (29) HO
Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff n~
(30) (31) HO
O ) (32) HO
(33) HO
O ~ O 'F
F
(34) Boehrin~ger Ingelheim Case 111558 ff 'F
(35) N \ / \ F
w HO
HO''~. '''OH
OH
O~ O
(36) ~ ~ \
HO
HO~~~ ~~~OH
OH
(37) (38) HO
(39) Boehringer Ingelhelrrl CA 02539032 2006-02-24 Case 1/1558 ff (40) (41) o~
(42) N~
O O
HO
HO~~~, ~~'OH
OH
(43) OH
(44) HO
Boehringer Ingelheim Case 1/1558 ff (45) (46) (47) (48) ~ 0 \N /
w F
o,,,. ''''o (49) HO
Boehringer Ingelheim Case 1/1558 ff (50) /
N \
N~
O O
HO
HO~~~' ~~~OH
OH
(51) (52) HC
OH
O
(53) (54) HO
HO
HO~~,~ ~~~OH
OH
Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 111558 ff (55) (56) (57) O
O O
HO
O ~O
N \
w O O
O'~~. ~~'O
O
(58) \~o (59) N \
o \ ~ O O
O o o'~~~ ~''o O
Boehringer Ingelheim Case 1/1558 ff o (60) (61) (62) ~//
1 f w O O
o o'~~~ ~''o o (63) F
O O
O
O'~~, ~~'O
O
O F
--~ ~ \ ~F
(64) N ~ \ ~ o o''~~ ~''o Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff o~
o>
(65) N ~ ~ ~ o o,,.. ''''o o~
(66) (67) (68) (~ o, (69) Boehringer Ingelhelftl CA 02539032 2006-02-24 Case 111558 ff o--~
(70) O~F
F
(71) (72) o, ~1 F
O O
O
0~~~~ ~~~0 O
(74) ~ o, 8oehringer Ifigeihelfl'1 CA 02539032 2006-02-24 Case 1/1558 ff (75) ~o C~ O F
(76) ~ F
O
/~O~O
(77) O
o, (78) (~
(79) ''-woo Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff The following are examples of formulations in which the phrase "active substance"
denotes one or more compounds according to the invention, including the salts thereof. In the case of one of the combinations with one or more other active substances the term "active substance" also includes the additional activE: substances.
Example A
Tablets containing 100 mg of active substance Composition:
1 tabNet contains:
active substance 100.0 mg lactose 80.0 mg corn starch 34.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate 2.0 mg 220.0 mg Method of Preparation:
The active substance, lactose and starch are mixed together and uniformly moistened with an aqueous solution of the polyvinylpyrrolidone. After the moist composition has been screened (2.0 mm mesh size) and dried in a rack-type drier at 50°C
it is screened again (1.5 mm mesh size) and the lubricant is added. The finished mixture is compressed to form tablets.
WE:ight of tablet: 220 mg Di<~meter: 10 mm, biplanar, facetted on both sides and notched on one side.
Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff Exam Ip a B
Tablets containing 150 ma of active substance Composition:
1 tablet contains:
active substance 150.0 mg powdered lactose 89.0 mg corn starch 40.0 mg colloidal silica 10.0 mg poly~rinylpyrrolidone 10.0 mg magnesium stearate 1.0 ma 300.0 mg Preparation:
The active substance mixed with lactose, corn starch and silica is moistened with a 20% aqueous polyvinylpyrrolidone solution and passed through a screen with a mesh size of 1.5 mm. The granules, dried at 45°C, are passed through the same screen again and mixed with the specified amount of magnesium stearate. Tablets are pressed from the mixture.
Vl~eight of tablet: 300 mg die: 10 mm, flat Exami~le C
Hard gelatine capsules containing 150 ma of active substance 1 cap:cule contains:
active substance150.0 mg corn starch (driedapprox. 180.0 mg lactose (powdered)approx. 87.0 mg magnesium stearate3.0 mg approx. 420.0 mg ~Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff Preparation:
The active substance is mixed with the excipients, passed through a screen with a mesh size of 0.75 mm and homogeneously mixed using a suitable apparatus. The finished mixture is packed into size 1 hard gelatine capsules.
Capsule filling: approx. 320 mg Capsule shell: size 1 hard gelatine capsule.
Exam I_p a D
Suppositories containing 150 ma of active substance 1 suppository contains:
active substance 150.0 mg polyethyleneglycol 1500 550.0 mg polyethyleneglycol 6000 460.0 mg polyoxyethylene sorbitan monostearate 840.0 mg 2,000.0 mg Preparation:
After the suppository mass has been melted the active substance is homogeneously distributed therein and the melt is poured into chilled moulds.
Exam-ple E
A~oules containing 10 mg active substance Composition:
aclrive substance 10.0 mg 0.C11 N hydrochloric acid q.s.
double-distilled water ad 2.0 ml Boehringer Ingelheltll CA 02539032 2006-02-24 Case 1/1558 ff Preparation:
The active substance is dissolved in the necessary amount of 0.01 N HCI, made isotonic with common salt, filtered sterile and transferred into 2 ml ampoules.
Example F
Ampoules containing 50 ma of active substance Composition:
active substance 50.0 mg 0.01 N hydrochloric acid q.s.
double-distilled water ad 10.0 ml Preparation:
The active substance is dissolved in the necessary amount of 0.01 N HCI, made isotonic with common salt, filtered sterile and transferred into 10 ml ampoules.
N
N
O O
O''~. ~~''O
O
Prepared by alkylation of the compound of Example VI(1 ) and subsequent hydrolysis of the acetyl groups analogously to Example V
Mass spectrum (ESI+): m/z = 479 [M+H]+
Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff The following compounds are also prepared analogously to the above-mentioned Examples and other methods known from the literature:
(10) HO
(11) HO
N
(12) N, HO
HO~~1,~.~~~OH
OH
O~~, ~N ~ I
(13) HO
HO~~~, ~~~OH
OH
O
~N
( 14) HO
HO~~~~ ~~~OH
OH
Boehrin~ger 111gelhelfll CA 02539032 2006-02-24 Case 111558 ff n~
(15) o'~
(16) ~o~o o~
(17) ~o~o ( 18) ri HO~~~~ ~~~OH
OH
(19) ~o Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 111b58 ff (20) o~
(21) N \
N~ -O
O O
~O~O
HO~~~, ~~~OH
OH
n~
(22) ~o~o (23) o~o OH
O
\~/ /
(24) N~
O O
HO
HO~~~' ~~~OH
OH
Case 1!1558 ff $Oehflfl9ef Ifl9elhelfll CA 02539032 2006-02-24 (25) HO
(26) HO
OH
(27) (28) (29) HO
Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff n~
(30) (31) HO
O ) (32) HO
(33) HO
O ~ O 'F
F
(34) Boehrin~ger Ingelheim Case 111558 ff 'F
(35) N \ / \ F
w HO
HO''~. '''OH
OH
O~ O
(36) ~ ~ \
HO
HO~~~ ~~~OH
OH
(37) (38) HO
(39) Boehringer Ingelhelrrl CA 02539032 2006-02-24 Case 1/1558 ff (40) (41) o~
(42) N~
O O
HO
HO~~~, ~~'OH
OH
(43) OH
(44) HO
Boehringer Ingelheim Case 1/1558 ff (45) (46) (47) (48) ~ 0 \N /
w F
o,,,. ''''o (49) HO
Boehringer Ingelheim Case 1/1558 ff (50) /
N \
N~
O O
HO
HO~~~' ~~~OH
OH
(51) (52) HC
OH
O
(53) (54) HO
HO
HO~~,~ ~~~OH
OH
Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 111558 ff (55) (56) (57) O
O O
HO
O ~O
N \
w O O
O'~~. ~~'O
O
(58) \~o (59) N \
o \ ~ O O
O o o'~~~ ~''o O
Boehringer Ingelheim Case 1/1558 ff o (60) (61) (62) ~//
1 f w O O
o o'~~~ ~''o o (63) F
O O
O
O'~~, ~~'O
O
O F
--~ ~ \ ~F
(64) N ~ \ ~ o o''~~ ~''o Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff o~
o>
(65) N ~ ~ ~ o o,,.. ''''o o~
(66) (67) (68) (~ o, (69) Boehringer Ingelhelftl CA 02539032 2006-02-24 Case 111558 ff o--~
(70) O~F
F
(71) (72) o, ~1 F
O O
O
0~~~~ ~~~0 O
(74) ~ o, 8oehringer Ifigeihelfl'1 CA 02539032 2006-02-24 Case 1/1558 ff (75) ~o C~ O F
(76) ~ F
O
/~O~O
(77) O
o, (78) (~
(79) ''-woo Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff The following are examples of formulations in which the phrase "active substance"
denotes one or more compounds according to the invention, including the salts thereof. In the case of one of the combinations with one or more other active substances the term "active substance" also includes the additional activE: substances.
Example A
Tablets containing 100 mg of active substance Composition:
1 tabNet contains:
active substance 100.0 mg lactose 80.0 mg corn starch 34.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate 2.0 mg 220.0 mg Method of Preparation:
The active substance, lactose and starch are mixed together and uniformly moistened with an aqueous solution of the polyvinylpyrrolidone. After the moist composition has been screened (2.0 mm mesh size) and dried in a rack-type drier at 50°C
it is screened again (1.5 mm mesh size) and the lubricant is added. The finished mixture is compressed to form tablets.
WE:ight of tablet: 220 mg Di<~meter: 10 mm, biplanar, facetted on both sides and notched on one side.
Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff Exam Ip a B
Tablets containing 150 ma of active substance Composition:
1 tablet contains:
active substance 150.0 mg powdered lactose 89.0 mg corn starch 40.0 mg colloidal silica 10.0 mg poly~rinylpyrrolidone 10.0 mg magnesium stearate 1.0 ma 300.0 mg Preparation:
The active substance mixed with lactose, corn starch and silica is moistened with a 20% aqueous polyvinylpyrrolidone solution and passed through a screen with a mesh size of 1.5 mm. The granules, dried at 45°C, are passed through the same screen again and mixed with the specified amount of magnesium stearate. Tablets are pressed from the mixture.
Vl~eight of tablet: 300 mg die: 10 mm, flat Exami~le C
Hard gelatine capsules containing 150 ma of active substance 1 cap:cule contains:
active substance150.0 mg corn starch (driedapprox. 180.0 mg lactose (powdered)approx. 87.0 mg magnesium stearate3.0 mg approx. 420.0 mg ~Boehringer Ingelhelnl CA 02539032 2006-02-24 Case 1/1558 ff Preparation:
The active substance is mixed with the excipients, passed through a screen with a mesh size of 0.75 mm and homogeneously mixed using a suitable apparatus. The finished mixture is packed into size 1 hard gelatine capsules.
Capsule filling: approx. 320 mg Capsule shell: size 1 hard gelatine capsule.
Exam I_p a D
Suppositories containing 150 ma of active substance 1 suppository contains:
active substance 150.0 mg polyethyleneglycol 1500 550.0 mg polyethyleneglycol 6000 460.0 mg polyoxyethylene sorbitan monostearate 840.0 mg 2,000.0 mg Preparation:
After the suppository mass has been melted the active substance is homogeneously distributed therein and the melt is poured into chilled moulds.
Exam-ple E
A~oules containing 10 mg active substance Composition:
aclrive substance 10.0 mg 0.C11 N hydrochloric acid q.s.
double-distilled water ad 2.0 ml Boehringer Ingelheltll CA 02539032 2006-02-24 Case 1/1558 ff Preparation:
The active substance is dissolved in the necessary amount of 0.01 N HCI, made isotonic with common salt, filtered sterile and transferred into 2 ml ampoules.
Example F
Ampoules containing 50 ma of active substance Composition:
active substance 50.0 mg 0.01 N hydrochloric acid q.s.
double-distilled water ad 10.0 ml Preparation:
The active substance is dissolved in the necessary amount of 0.01 N HCI, made isotonic with common salt, filtered sterile and transferred into 10 ml ampoules.
Claims (16)
1. Glucopyranosyloxy-pyrazoles of general formula wherein R1 denotes C3-6-alkynyl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuranyl-C1-3-alkyl, tetrahydropyranyl-C1-3-alkyl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, or a pyrrolidin-3-yl, piperidin-3-yl or piperidin-4-yl group, while in the latter three groups the nitrogen atom may be substituted by a C1-4-alkyl, formyl, C1-4-alkyl-carbonyl, C1-4-alkylsulphonyl, cyano, aminocarbonyl, (C1-4-alkyl)-aminocarbonyl, di-(C1-4-alkyl)-aminocarbonyl or (C1-4-alkyl)-oxycarbonyl group, or if R3 (a) is selected from one of the definitions of the group A; or (b) together with R4 denotes difluoromethylenedioxy; or (c) denotes C3-6-cycloalkyl-oxy or C3-6-cycloalkylidene-methyl and simultaneously R4 denotes fluorine, chlorine, bromine, C1-3-alkyl, C1-3-alkoxy or a methyl or methoxy group substituted by 1 to 3 fluorine atoms;
then R1 may also represent hydrogen, C1-6-alkyl, a C1-4-alkyl group substituted by 1 to 3 fluorine atoms, a C2-4-alkyl group substituted by a hydroxy or C1-3-alkoxy group, or C3-6-alkenyl, C3-6-cycloalkyl, C3-6-cycloalkyl-C1-3-alkyl, aryl or aryl-C1-3-alkyl, and R2 denotes C1-4-alkyl, a C1-4-alkyl group substituted by 1 to 3 fluorine atoms, or C3-6-cycloalkyl, and R3 denotes hydrogen, fluorine, chlorine, bromine, iodine, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-6-cycloalkyl, C3-6-cycloalkylidenemethyl, C1-6-alkoxy, C3-6-cycloalkyl-oxy, C3-6-cycloalkyl-C1-3-alkoxy, aryl, aryl-C1-3-alkyl, heteroaryl, heteroaryl-C1-3-alkyl, aryloxy, aryl-C1-3-alkyl-oxy, a methyl or methoxy group substituted by 1 to 3 fluorine atoms, a C2-4-alkyl or C2-4-alkoxy group substituted by 1 to 5 fluorine atoms, a C1-4-alkyl group substituted by a cyano group, a C1-4-alkyl group substituted by a hydroxy or C1-3-alkyloxy group, or cyano, carboxy, C1-3-alkoxycarbonyl, aminocarbonyl, (C1-3-alkylamino)carbonyl, di-(C1-3-alkyl)aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-yl-carbonyl, 4-(C1-alkyl)-piperazin-1-ylcarbonyl, nitro, amino, C1-3-alkylamino, di-(C1-3-alkyl)amino, (C1-4-alkyl)carbonylamino, C1-4-alkylsulphonylamino, arylsulphonylamino, aryl-C1-3-alkylsulphonylamino, C1-4-alkylsulphanyl, C1-4-alkylsulphinyl, C1-4-alkylsulphonyl, arylsulphenyl, arylsulphinyl or arylsulphonyl, or has a meaning selected from the group A, and R4 and R5, which may be identical or different, represent hydrogen, fluorine, chlorine, bromine, C1-3-alkyl, C1-3-alkoxy, a methyl or methoxy group substituted by 1 to 3 fluorine atoms, or R3 together with R4, if they are bound to adjacent carbon atoms, may also represent a straight-chain C3-5-alkylene, a methylenedioxy or difluoromethylenedioxy bridge, and R6, R7a, R7b, R7c independently of one another have a meaning selected from the group hydrogen, (C1-18-alkyl)carbonyl, (C1-18-alkyl)oxycarbonyl, arylcarbonyl and aryl-(C1-3-alkyl)-carbonyl, A is selected from the group consisting of tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl-C1-3-alkoxy, tetrahydropyranyl-C1-3-alkoxy, pyrrolidin-3-yloxy, piperidin-3-yloxy, piperidin-4-yloxy group, and pyrrolidin-3-yloxy, piperidin-3-yloxy- and piperidin-4-yloxy, while in the latter three groups the nitrogen atom may be substituted by C1-4-alkyl, formyl, C1-4-alkyl-carbonyl, C1-4-alkylsulphonyl, cyano, aminocarbonyl, (C1-4-alkyl)-aminocarbonyl, di-(C1-4-alkyl)-aminocarbonyl or (C1-4-alkyl)-oxycarbonyl, while the aryl groups mentioned in the definition of the above groups are meant to indicate phenyl or naphthyl groups which may be mono- or disubstituted independently of one another by R h, while the substituents may be identical or different and R h denotes a fluorine, chlorine, bromine, iodine, C1-3-alkyl, difluoromethyl, trifluoromethyl, C1-3-alkoxy, difluoromethoxy, trifluoromethoxy or cyano, the heteroaryl groups mentioned in the definition of the above-mentioned groups are meant to indicate a pyrrolyl, furanyl, thienyl, pyridyl, indolyl, benzofuranyl, benzothio-phenyl, quinolinyl or isoquinolinyl group, or a pyrrolyl, furanyl, thienyl or pyridyl group, wherein one or two methyne groups are replaced by nitrogen atoms, or an indolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl group, wherein one to three methyne groups are replaced by nitrogen atoms, while the above-mentioned heteroaryl groups may be mono- or disubstituted by R
h, while the substituents may be identical or different and R h is as hereinbefore defined, while, unless otherwise stated, the above-mentioned alkyl groups may be straight-chain or branched, the tautomers, the stereoisomers, the mixtures thereof and the salts thereof.
then R1 may also represent hydrogen, C1-6-alkyl, a C1-4-alkyl group substituted by 1 to 3 fluorine atoms, a C2-4-alkyl group substituted by a hydroxy or C1-3-alkoxy group, or C3-6-alkenyl, C3-6-cycloalkyl, C3-6-cycloalkyl-C1-3-alkyl, aryl or aryl-C1-3-alkyl, and R2 denotes C1-4-alkyl, a C1-4-alkyl group substituted by 1 to 3 fluorine atoms, or C3-6-cycloalkyl, and R3 denotes hydrogen, fluorine, chlorine, bromine, iodine, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-6-cycloalkyl, C3-6-cycloalkylidenemethyl, C1-6-alkoxy, C3-6-cycloalkyl-oxy, C3-6-cycloalkyl-C1-3-alkoxy, aryl, aryl-C1-3-alkyl, heteroaryl, heteroaryl-C1-3-alkyl, aryloxy, aryl-C1-3-alkyl-oxy, a methyl or methoxy group substituted by 1 to 3 fluorine atoms, a C2-4-alkyl or C2-4-alkoxy group substituted by 1 to 5 fluorine atoms, a C1-4-alkyl group substituted by a cyano group, a C1-4-alkyl group substituted by a hydroxy or C1-3-alkyloxy group, or cyano, carboxy, C1-3-alkoxycarbonyl, aminocarbonyl, (C1-3-alkylamino)carbonyl, di-(C1-3-alkyl)aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-yl-carbonyl, 4-(C1-alkyl)-piperazin-1-ylcarbonyl, nitro, amino, C1-3-alkylamino, di-(C1-3-alkyl)amino, (C1-4-alkyl)carbonylamino, C1-4-alkylsulphonylamino, arylsulphonylamino, aryl-C1-3-alkylsulphonylamino, C1-4-alkylsulphanyl, C1-4-alkylsulphinyl, C1-4-alkylsulphonyl, arylsulphenyl, arylsulphinyl or arylsulphonyl, or has a meaning selected from the group A, and R4 and R5, which may be identical or different, represent hydrogen, fluorine, chlorine, bromine, C1-3-alkyl, C1-3-alkoxy, a methyl or methoxy group substituted by 1 to 3 fluorine atoms, or R3 together with R4, if they are bound to adjacent carbon atoms, may also represent a straight-chain C3-5-alkylene, a methylenedioxy or difluoromethylenedioxy bridge, and R6, R7a, R7b, R7c independently of one another have a meaning selected from the group hydrogen, (C1-18-alkyl)carbonyl, (C1-18-alkyl)oxycarbonyl, arylcarbonyl and aryl-(C1-3-alkyl)-carbonyl, A is selected from the group consisting of tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl-C1-3-alkoxy, tetrahydropyranyl-C1-3-alkoxy, pyrrolidin-3-yloxy, piperidin-3-yloxy, piperidin-4-yloxy group, and pyrrolidin-3-yloxy, piperidin-3-yloxy- and piperidin-4-yloxy, while in the latter three groups the nitrogen atom may be substituted by C1-4-alkyl, formyl, C1-4-alkyl-carbonyl, C1-4-alkylsulphonyl, cyano, aminocarbonyl, (C1-4-alkyl)-aminocarbonyl, di-(C1-4-alkyl)-aminocarbonyl or (C1-4-alkyl)-oxycarbonyl, while the aryl groups mentioned in the definition of the above groups are meant to indicate phenyl or naphthyl groups which may be mono- or disubstituted independently of one another by R h, while the substituents may be identical or different and R h denotes a fluorine, chlorine, bromine, iodine, C1-3-alkyl, difluoromethyl, trifluoromethyl, C1-3-alkoxy, difluoromethoxy, trifluoromethoxy or cyano, the heteroaryl groups mentioned in the definition of the above-mentioned groups are meant to indicate a pyrrolyl, furanyl, thienyl, pyridyl, indolyl, benzofuranyl, benzothio-phenyl, quinolinyl or isoquinolinyl group, or a pyrrolyl, furanyl, thienyl or pyridyl group, wherein one or two methyne groups are replaced by nitrogen atoms, or an indolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl group, wherein one to three methyne groups are replaced by nitrogen atoms, while the above-mentioned heteroaryl groups may be mono- or disubstituted by R
h, while the substituents may be identical or different and R h is as hereinbefore defined, while, unless otherwise stated, the above-mentioned alkyl groups may be straight-chain or branched, the tautomers, the stereoisomers, the mixtures thereof and the salts thereof.
2. Glucopyranosyloxy-pyrazoles of general formula I according to claim 1, wherein R1 denotes 2-propyn-1-yl, 2-butyn-1-yl, tetrahydrofuran-3-yl, tetrahydropyran-
3-yl, tetrahydropyran-4-yl, tetrahydrofuranylmethyl or tetrahydropyranylmethyl, or, if R3 (a) is selected from the group consisting of tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethyloxy and tetrahydropyranylmethyloxy, or (b) together with R4 denotes a difluoromethylenedioxy bridge, or, (c) denotes cylopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclopropylidenemethyl and R4 simultaneously denotes fluorine, then R1 may also represent isopropyl, and R2 denotes methyl or trifluoromethyl, R3 denotes hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, tert.-butyl, 2-cyano-2-propyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, cylopropyl-oxy, cyclobutyl-oxy, cyclopentyl-oxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethyloxy, tetrahydropyranylmethyloxy, methylsulphanyl, 2-methyl-1-propen-1-yl, cyclopropylidenemethyl, ethynyl, phenyl, fluorophenyl, pyridyl or methylthiazolyl, and R4 denotes hydrogen or fluorine, or R3 together with R4, if they are bound to adjacent carbon atoms, may also represent a 1,3-propylene, methylenedioxy or difluoromethylenedioxy bridge, and R5 denotes hydrogen and R6 denotes hydrogen, (C1-8-alkyl)oxycarbonyl or C1-8-alkylcarbonyl, the tautomers, the stereoisomers, the mixtures thereof and the salts thereof.
3. Glucopyranosyloxy-pyrazoles of general formula I according to claim 1, wherein R1 denotes 2-propyn-1-yl, 2-butyn-1-yl, tetrahydrofuran-3-yl, tetrahydropyran-
3. Glucopyranosyloxy-pyrazoles of general formula I according to claim 1, wherein R1 denotes 2-propyn-1-yl, 2-butyn-1-yl, tetrahydrofuran-3-yl, tetrahydropyran-
4-yl or tetrahydrofuran-2-ylmethyl or, if R3 is selected from the group consisting of tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy and tetrahydrofuranylmethyloxy, then R1 may also isopropyl represent, R2 denotes methyl, R3 denotes methyl, ethyl, methoxy, ethoxy, difluoromethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy or tetrahydrofuranylmethyloxy, R4 denotes hydrogen or fluorine, R5 denotes hydrogen and R6 denotes hydrogen, methoxycarbonyl or ethoxycarbonyl, the tautomers, the stereoisomers, the mixtures thereof and the salts thereof.
4. Glucopyranosyloxy-pyrazoles of general formula I according to claim 1, wherein R1 denotes tetrahydrofuran-3-yl or tetrahydropyran-4-yl, R2 denotes methyl, R3 denotes methyl, ethyl, methoxy, ethoxy or difluoromethoxy, R4 denotes hydrogen or fluorine, R5 denotes hydrogen, R6 denotes hydrogen, methoxycarbonyl or ethoxycarbonyl and R7a, R7b and R7c denote hydrogen, the tautomers, the stereoisomers, the mixtures thereof and the salts thereof.
4. Glucopyranosyloxy-pyrazoles of general formula I according to claim 1, wherein R1 denotes tetrahydrofuran-3-yl or tetrahydropyran-4-yl, R2 denotes methyl, R3 denotes methyl, ethyl, methoxy, ethoxy or difluoromethoxy, R4 denotes hydrogen or fluorine, R5 denotes hydrogen, R6 denotes hydrogen, methoxycarbonyl or ethoxycarbonyl and R7a, R7b and R7c denote hydrogen, the tautomers, the stereoisomers, the mixtures thereof and the salts thereof.
5. Compounds of general formula I according to claim 1 selected from the group consisting of (a) 1-(2-propyn-1-yl)-3-(.beta.-D-glucopyranosyloxy)-4-(4-ethylbenzyl)-5-methyl-1H-pyrazole, (b) 1-(2-propyn-1-yl)-3-(6-O-methoxycarbonyl-.beta.-D-glucopyranosyloxy)-4-(4-ethylbenzyl)-5-methyl-1H-pyrazole, (c) 1-((S)-tetrahydrofuran-3-yl)-3-(.beta.-D-glucopyranosyloxy)-4-(4-ethylbenzyl)-5-methyl-1H-pyrazole, (d) 1-(tetrahydropyran-4-yl)-3-(.beta.-D-glucopyranosyloxy)-4-(4-ethylbenzyl)-5-methyl-1H-pyrazole, (e) 1-isopropyl-3-(.beta.-D-glucopyranosyloxy)-4-[4-((S)-tetrahydrofuran-3-yloxy)benzyl]-5-methyl-1H-pyrazole, (f) 1-isopropyl-3-(.beta.-D-glucopyranosyloxy)-4-[4-((R)-tetrahydrofuran-3-yloxy)benzyl]-5-methyl-1 H-pyrazole, (g) 1-(tetrahydropyran-4-yl)-3-(.beta.-D-glucopyranosyloxy)-4-(4-methoxybenzyl)-5-methyl-1H-pyrazole, and the derivatives thereof, wherein R6 has a meaning according to the invention other than hydrogen, and in particular R6 denotes ethoxycarbonyl or methoxycarbonyl, including the tautomers, the stereoisomers, the mixtures thereof and the salts thereof.
6. Physiologically acceptable salts of the compounds according to at least one of claims 1 to 5 with inorganic or organic acids.
7. Use of a compound according to one or more of claims 1 to 5 or a physiologically acceptable salt according to claim 6, as a pharmaceutical composition.
8. Pharmaceutical composition, containing a compound according to one or more of claims 1 to 5 or a physiologically acceptable salt according to claim 6, optionally together with one or more inert carriers and/or diluents.
9. Use of at least one compound according to one or more of claims 1 to 5 or a physiologically acceptable salt according to claim 6 for preparing a pharmaceutical composition which is suitable for the treatment or prevention of diseases or conditions which can be influenced by inhibiting the sodium-dependent glucose cotransporter SGLT.
10. Use of at least one compound according to one or more of claims 1 to 5 or a physiologically acceptable salt according to claim 6 for preparing a pharmaceutical composition which is suitable for the treatment or prevention of metabolic disorders.
11. Use according to claim 10, characterised in that the metabolic disorder is selected from the group consisting of type 1 and type 2 diabetes mellitus, complications of diabetes, metabolic acidosis or ketosis, reactive hypoglycaemia, hyperinsulinaemia, glucose metabolic disorder, insulin resistance, metabolic syndrome, dyslipidaemias of different origins, atherosclerosis and related diseases, obesity, high blood pressure, chronic heart failure, oedema and hyperuricaemia.
12. Use of at least one compound according to at least one of claims 1 to 5 or a physiologically acceptable salt according to claim 6 for preparing a pharmaceutical composition for inhibiting the sodium-dependent glucose cotransporter SGLT.
13. Use of at least one compound according to at least one of claims 1 to 5 or a physiologically acceptable salt according to claim 6 for preparing a pharmaceutical composition for preventing the degeneration of pancreatic beta cells and/or for improving and/or restoring the functionality of pancreatic beta cells.
14. Use of at least one compound according to at least one of claims 1 to 5 or a physiologically acceptable salt according to claim 6 for preparing diuretics and/or antihypertensives.
15. Process for preparing a pharmaceutical composition according to claim 8, characterised in that a compound according to at least one of claims 1 to 5 or a physiologically acceptable salt according to claim 6 is incorporated in one or more inert carriers and/or diluents by a non-chemical method.
16. Process for preparing the compounds of general formula I according to claims 1 to 5, characterised in that a) in order to prepare compounds of general formula I wherein R1 denotes one of the groups mentioned in claims 1 to 5 but does not denote a hydrogen atom, a compound of general formula wherein R2 to R6 and R7a, R7b, R7c are defined as in claims 1 to 5, is reacted with a compound of general formula Z1-R1' (III), wherein R1' has the meanings given for R1 hereinbefore, but does not denote a hydrogen atom, and Z1 denotes a leaving group, or b) in order to prepare compounds of general formula I wherein R3 denotes optionally substituted C1-6-alkoxy, C3-6-cycloalkyl-oxy, C3-5-cycloalkyl-C1-3-alkoxy or has a meaning selected from the group A, which is defined according to claim 1, a compound of general formula wherein R1, R2 and R4 to R5 and R7a, R7b, R7c are defined as in claim 1, is reacted with a compound of general formula Z2-R3, (V), wherein R3' denotes optionally substituted C1-6-alkoxy, C3-6-cycloalkyl-oxy, C3-5-cycloalkyl-C1-3-alkoxy or has a meaning selected from the group A, which is as hereinbefore defined, and Z2 denotes a leaving group, preferably a halogen atom, for example a chlorine or bromine atom, a sulphonyloxy group, for example a methanesulphonyloxy or p-toluenesulphonyloxy group or a hydroxy group, and if desired a compound of general formula I thus obtained wherein R6 denotes a hydrogen atom, is converted by acylation into a corresponding acyl compound of general formula I, and/or if necessary any protecting group used during the reactions described above is cleaved again and/or if desired a compound of general formula I thus obtained is resolved into its stereoisomers and/or a compound of general formula I thus obtained is converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts thereof.
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DE10339549.0 | 2003-08-26 | ||
DE10339549A DE10339549A1 (en) | 2003-08-26 | 2003-08-26 | New glucopyranosyloxy-pyrazole derivatives are sodium dependent glucose cotransporter inhibitors used for treating and preventing metabolic disorders, particularly diabetes |
DE10359960A DE10359960A1 (en) | 2003-12-18 | 2003-12-18 | New glucopyranosyloxy-pyrazole derivatives are sodium dependent glucose cotransporter inhibitors used for treating and preventing metabolic disorders, particularly diabetes |
DE10359960.6 | 2003-12-18 | ||
PCT/EP2004/009332 WO2005021566A2 (en) | 2003-08-26 | 2004-08-20 | Glucopyranosyloxy- pirazoles, drugs containing said compounds the use and production method thereof |
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WO2002068440A1 (en) * | 2001-02-27 | 2002-09-06 | Kissei Pharmaceutical Co., Ltd. | Glycopyranosyloxypyrazole derivatives and medicinal use thereof |
CA2672001A1 (en) * | 2001-04-27 | 2002-11-07 | Ajinomoto Co., Inc. | N-substituted pyrazole-o-glycoside derivatives and therapeutic agent for diabetes containing the same |
US7217697B2 (en) * | 2001-05-30 | 2007-05-15 | Kissei Pharmaceutical Co., Ltd. | Glucopyranosyloxypyrazole derivative medicinal composition containing the same medicinal use thereof and intermediate therefor |
JP4115105B2 (en) * | 2001-07-02 | 2008-07-09 | 協和醗酵工業株式会社 | Pyrazole derivative |
US20030087843A1 (en) * | 2001-09-05 | 2003-05-08 | Washburn William N. | O-pyrazole glucoside SGLT2 inhibitors and method of use |
-
2004
- 2004-08-20 EP EP04764316A patent/EP1660509B1/en not_active Not-in-force
- 2004-08-20 DE DE502004008951T patent/DE502004008951D1/en active Active
- 2004-08-20 WO PCT/EP2004/009332 patent/WO2005021566A2/en active Application Filing
- 2004-08-20 CA CA002539032A patent/CA2539032A1/en not_active Withdrawn
- 2004-08-20 AT AT04764316T patent/ATE422204T1/en active
- 2004-08-20 ES ES04764316T patent/ES2322059T3/en active Active
- 2004-08-20 JP JP2006524303A patent/JP4520988B2/en not_active Expired - Fee Related
- 2004-08-23 UY UY28489A patent/UY28489A1/en not_active Application Discontinuation
- 2004-08-24 PE PE2004000813A patent/PE20050346A1/en not_active Application Discontinuation
- 2004-08-25 AR ARP040103047A patent/AR045490A1/en not_active Suspension/Interruption
- 2004-08-26 TW TW093125661A patent/TW200526679A/en unknown
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Also Published As
Publication number | Publication date |
---|---|
AR045490A1 (en) | 2005-11-02 |
JP4520988B2 (en) | 2010-08-11 |
ATE422204T1 (en) | 2009-02-15 |
ES2322059T3 (en) | 2009-06-16 |
PE20050346A1 (en) | 2005-06-15 |
DE502004008951D1 (en) | 2009-03-19 |
JP2007503413A (en) | 2007-02-22 |
WO2005021566A2 (en) | 2005-03-10 |
UY28489A1 (en) | 2005-03-31 |
EP1660509B1 (en) | 2009-02-04 |
EP1660509A2 (en) | 2006-05-31 |
WO2005021566A3 (en) | 2005-04-07 |
TW200526679A (en) | 2005-08-16 |
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