MXPA01004826A - Combinations comprising a beta-agonist and a further antidiabetic agent - Google Patents
Combinations comprising a beta-agonist and a further antidiabetic agentInfo
- Publication number
- MXPA01004826A MXPA01004826A MXPA/A/2001/004826A MXPA01004826A MXPA01004826A MX PA01004826 A MXPA01004826 A MX PA01004826A MX PA01004826 A MXPA01004826 A MX PA01004826A MX PA01004826 A MXPA01004826 A MX PA01004826A
- Authority
- MX
- Mexico
- Prior art keywords
- yloxy
- antidiabetic agent
- insulin
- ethylamino
- hydroxyethyl
- Prior art date
Links
- 239000000556 agonist Substances 0.000 title claims abstract description 44
- 239000003472 antidiabetic agent Substances 0.000 title claims abstract description 39
- 206010012601 Diabetes mellitus Diseases 0.000 claims abstract description 26
- 241000124008 Mammalia Species 0.000 claims abstract description 5
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 88
- 239000000203 mixture Substances 0.000 claims description 47
- -1 glyclopramide Chemical compound 0.000 claims description 45
- 102000004877 Insulin Human genes 0.000 claims description 44
- 108090001061 Insulin Proteins 0.000 claims description 44
- 150000001875 compounds Chemical class 0.000 claims description 42
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- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical compound O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 claims description 8
- HYAFETHFCAUJAY-UHFFFAOYSA-N Pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 claims description 8
- GXPHKUHSUJUWKP-UHFFFAOYSA-N Troglitazone Chemical group C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)COC(C=C1)=CC=C1CC1SC(=O)NC1=O GXPHKUHSUJUWKP-UHFFFAOYSA-N 0.000 claims description 7
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- NWWORXYTJRPSMC-QKPAOTATSA-N ethyl 4-[2-[(2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl]ethoxy]benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1OCCN1[C@H](CO)[C@@H](O)[C@H](O)[C@@H](O)C1 NWWORXYTJRPSMC-QKPAOTATSA-N 0.000 claims description 3
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- PDPBIXXIHOWWHA-UHFFFAOYSA-N 2-benzyl-3,4-dihydro-2H-chromene Chemical compound C1CC2=CC=CC=C2OC1CC1=CC=CC=C1 PDPBIXXIHOWWHA-UHFFFAOYSA-N 0.000 claims description 2
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Abstract
A method for the treatment of diabetes mellitus and conditions associated with diabetes mellitus in a mammal such as a human, which method comprises administering an effective, non-toxic and pharmaceutically acceptable amount of a beta agonist and another antidiabetic agent, to a mammal in need thereof.
Description
COMBINATIONS THAT INCLUDE A BETA AGONIST AND AN ADDITIONAL ANTIDIABETIC AGENT
DESCRIPTIVE MEMORY
This invention relates to a method of treatment, in particular to a method for the treatment of diabetes mellitus, especially diabetes that does not depend on insulin (NIDDM) or Type 2 diabetes and conditions associated with diabetes mellitus, and to compositions for use in such a method. . Alpha-glucosidase-inhibiting antihyperglycemic agents (or alpha glucosidase inhibitors) and biguanide antihyperglycemic agents (or biguanides) are commonly used in the treatment of Type 2 diabetes. Acarbose, voglibose, emiglitate and miglitol are examples of alpha glucosidase inhibitors. 1,1-dimethylbiguanidine (or metformin) is a particular example of a biguanide. Insulin secretagogues are compounds that promote the increased secretion of insulin by pancreatic beta cells. Sulfonylureas are well-known examples of insulin secretagogues. Sulfonylureas act as hypoglycemic agents and are used in the treatment of Type 2 diabetes. Examples of sulfonylureas include glibenclamide (or glyburide), glipizide, gliclazide, glimepiride, tolazamide and tolbutamide. European patent application, publication number 0,306,228 relates to certain thiazolidinedione derivatives described as having antihyperglycemic and hypolipidemic activity. A particular thiazolidinedione described in EP 0306228 is 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione (hereinafter "Compound (I) "). WO94 / 05659 describes certain salts of Compound (I) which include the maleate salt in example 1 thereof. Compound (I) is an example of a class of antihyperglycemic agents known as "insulin sensitizers". In particular, the compound (I) is a thiazolidinedione insulin sensitizer. Compound (I) is also an insulin sensitizer peroxisome proliferator activated receptor agonist (PPAR?). European patent applications, publication numbers: 0008203,
0139421, 0032128, 0428312, 0489663, 0155845, 0257781, 0208420, 0177353, 0319189, 0332331, 0332332, 0528734, 0508740; International patent application, publication numbers 92/18501, 93/02079, 93/22445 and patent numbers of E.U.A. 5104888 and 5478852, also disclose certain thiazolidinedione insulin sensitizers. Another series of compounds generally recognized to have insulin sensitizing activity are those typified by the compounds described in the international patent applications, publication numbers WO93 / 21166 and WO94 / 01420. These compounds are referred to herein as "acyclic insulin sensitizers". Other examples of acyclic insulin sensitizers are those described in patent number E.U.A. 5232945 and international patent applications, publication numbers WO92 / 03425 and WO91 / 19702.
Examples of other insulin sensitizers are those described in the European patent application, publication number 0533933, Japanese patent application publication number 05271204 and patent number of E.U.A. 5264451. International patent application, publication number WO97 / 25311 and European patent application publication number EP0882707A1 refer to certain ethanolamine derivatives of formula (I):
or a salt thereof, wherein R represents hydrogen or methyl atom, R1 represents hydrogen atom, halogen atom, hydroxy, benzyloxy, amino or hydroxymethyl, R2 means hydrogen atom, hydroxymethyl, NHR3, SO2NR4R4, or nitro, wherein R3 is a hydrogen atom, methyl, SO2R5, formyl or CONHR6 ', where R5 is a lower alkyl, benzyl or NR4R4 \ and R6, being a hydrogen atom or lower alkyl, and R4 and R4' may be identical or different from each other; yes and each means hydrogen atom, lower alkyl or benzyl, R6 represents hydrogen atom or lower alkylX represents - a secondary nitrogen atom, oxygen atom, sulfur atom or methylene and, in case X is a secondary nitrogen atom, oxygen atom or sulfur atom, R9 represents hydrogen atom and any of R7 and R8 is a hydrogen atom and the other is a hydrogen, amino, acetylamino or hydroxy atom, or in the case where X is methylene, both R7 and R8 are hydrogen atoms and R9 means hydrogen, amino, acetylamino or hydroxy, * 1 indicates an asymmetric carbon atom and * 2 indicates that the carbon atom is asymmetric since R6 is lower alkyl. The compounds of W097 / 25311 and EP08827707A1 are mentioned for having beta 3 adrenoreceptor agonist activity and are described as being useful for the treatment and prevention of diabetes, hyperlipidemia and obesity. The aforementioned publications are incorporated herein by reference. It is now indicated that the beta 3 adrenoreceptor agonist compounds of WO97 / 25311 and EP0882707A1 in combination with other antidiabetic agents, provide a particularly beneficial effect on glycemic control and that such a combination is therefore suggested as being particularly useful for the treatment of diabetes mellitus, especially type 2 diabetes and conditions associated with diabetes mellitus. Such combinations will provide improved blood glucose regulation without introducing unacceptable side effects. In particular, the combination of the beta 3 -adrenoreceptor agonist with other antidiabetic agents (especially sulfonylureas, insulin sensitizers or insulin) is expected to reduce the effects that increase body weight of the other antidiabetic agents. Moreover, it is considered that the beneficial thermogenic effects of the beta-3 agonist will be improved in the combination. Thus, for example, the weight-reducing effects of the beta-3 agonist are expected to increase.
Accordingly, the invention provides a method for the treatment of diabetes mellitus, especially Type 2 diabetes and conditions associated with diabetes mellitus in a mammal such as a human, which method comprises administering an effective, non-toxic and pharmaceutically acceptable amount of an agonist. beta and another antidiabetic agent, to a mammal in need thereof. In another aspect, the invention provides a beta agonist and another antidiabetic agent, for use in method for the treatment of diabetes mellitus, especially type 2 diabetes and conditions associated with diabetes mellitus. The method comprises either the co-administration of a beta agonist and another antidiabetic agent or the consecutive administration thereof. Co-administration includes administration of a formula which includes either a beta agonist or the other antidiabetic agent or the essentially simultaneous administration of separate formulations of each agent. In another aspect, the invention provides the use of a beta agonist and the other antidiabetic agent for use in the preparation of a composition for the treatment of obesity, diabetes mellitus, especially Type 2 diabetes and conditions associated with diabetes mellitus. Suitably, the other antidiabetic agent is selected from an alpha glucosidase inhibitor, a biguanide, an insulin secretagogue or an insulin sensitizer. An additional suitable antidiabetic agent is insulin.
A suitable alpha glucosidase inhibitor is acarbose. Other suitable alpha glucosidase inhibitors are emiglitate, and miglitol. An additional suitable alpha glucosidase inhibitor is voglibose. Suitable biguanides include metformin, buformin or phenformin, especially metformin. Suitable insulin secretagogues include sulfonylureas. Suitable sulfonylureas include glibenclamide, glipizide, gliclazide, glimepiride, tolazamide and tolbutamide. In addition, the sulfonylureas include acetohexamide, carbutamide, chloropropamide, glibomuride, gliquidone, glisentide, glisolamide, glisoxepide, glyclopramide and glycylamide. Sulfonylurea glipentide is also included. An additional adequate insulin secretagogue is repaglinide. An additional insulin secretagogue is nateglinide. Insulin sensitisers include PPAR? Agonist insulin sensitizers. The insulin sensitizers also include thiazolidinedione insulin sensitizers. A preferred insulin sensitizer is the compound (I) or a derivative thereof. Other suitable thiazolidinedione insulin sensitizers include (+) - 5 - [[4 - [(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl) methoxy] phenyl] methyl] -2,4-thiazolidinedione (or troglitazone), 5- [4 - [(1-methylcyclohexyl) methoxy] benzyl] thiazolidin-2,4-dione (or ciglitazone), 5- [4- [2- (5-ethylpyridin-2-yl) ethoxy] benzyl] thiazolidine-2,4-dione (or pioglitazone) or 5 - [(2-benzyl-2,3-dihydrobenzopyran) -5-methyl) -thiazolidine-2,4-dione (or englitazone). A particular thiazolidinedione insulin sensitizer is 5- [4- [2- (5-ethylpyridin-2-yl) ethoxy] benzyl] thiazolidine-2,4-dione (or pioglitazone). A particular thiazolidinedione insulin sensitizer is (+) - 5 - [[4 - [(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl) methoxy] phenyl] methyl] -2,4-thiazolidinedione (or troglitazone). In particular, beta agonists are selective for the beta receptor
3 human. In particular, beta agonists have minimal effects in terms of human beta 1 and / or beta 2 receptors, thus producing minimal side effects mediated by beta 1 and / or beta 2. Side effects mediated by beta 2 include tremor, hypokalemia and vasodilatation, which can result in tachycardia. Side effects mediated by beta 1 include tachycardia. A suitable beta agonist is a compound of formula (I) of
WO / 9725311. Particular beta agonists include the specific examples described in WO / 9725311 and EP0882707A1, whose documents are incorporated herein by reference. A particular compound of WO / 9725311 or EP0882707A1 is selected from the list consisting of: (R) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl ] -2-hydroxyphenyl] methanesulfonamide, (S) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl-methanesulfonamide, N- [5- [ 2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl-methanesulfonamide, N- [5- [2- [2- (3-hydroxy-9H-carbazole-2- iloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl-methanesulfonamide, N- [5- [2- [2- (3-amino-9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2- hydroxyphenyl-methanesulfonamide, N- [5- [2- [2- (6-amino-9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl-methanesulfonamide, N- [5- [2- [2 - (6-hydroxy-9H-carbazol-2-yloxy) ethylamine-1-hydroxyethyl] -2-hydroxyphenyl-methanesulfonamide, (R) -N- [3- [2- [2- (9H-carbazole-2 -yloxy) ethylamino] -1- hydroxyethyl] phenyl] methanesulfonamide, (S) -N- [3- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl-phenyl] methanesulfonamide, N- [ 3- [2- [2- (9H-carbazole -2-yloxy) ethylamino] -1-hydroxyethyl] phenyl] methanesulfonamide, N-methyl-3- [2- [2- (9H-carbazol-2-yloxy) et.lamino] -1-hydroxoethyl] benzenesulfonamide, N- methyl- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxoethyl] -2-hydroxy-benzenesulfonamide, (R) -N- [5- [2- [2- (dibenzofuran- 3-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl-methanesulfonamide, (S) -N- [5- [2- [2- (dibenzofuran-3-yloxy) ethylamino] -1-hydroxyethyl] -2- hydroxyphenyl-methanesulfonamide, N- [5- [2- [2- (dibenzofuran-3-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl-methanesulfonamide, N- [5- [2- [2- (9H-carbazole-2- iloxy) ethylamino] -1-hydroxyethyl] -2- (benzyloxy) phenyl] methanesulfonamide, N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2 -chlorophenyl-methanesulfonamide, N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-fluorophenyl-methanesulfonamide, N- [3- [2- [2- (dibenzofuran-3 -ilox!) ethylamino] -1-hydroxyethyl] -phenyl-methanesulfonamide, N- [5- [2- [2- (7-acetylaminofluoren-2-yloxy) et-amino] -1-hydroxyethyl] -2-hydroxyphenyl-methanesulfonamines da, N- [5- [2- [2- (7-aminofluoren-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl-methanesulfonamide, N- [3- [2- [2- (7- acetylaminofiuoren-2-yloxy) ethylamino] -1-hydroxyethyl] phenyl] methanesulfonamide, N- [3- [2- [2- (7-aminofluoren-2-yloxy) ethylamino] -1-hydroxyethyl] phenyl] methanesulfonamide, N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl-formamide, N- [3- [2- [2- (9H-carbazole-2- iloxy) et.lamino] -1-hydroxyethyl] phenyl] formamide, N- [3- [2 - [[1- (9H-carbazol-2-yloxy) propan-2R-yl] amino] -1-hydroxyethyl ] phenyl] methanesulfonamide, 2- [N- [2- (9H-carbazol-2-yloxy) ethyl] amino] -1- (4-hydroxy-3-nitrophenyl) ethanol, 2- [N- [2- (9H -carbazol-2-yloxy) ethyl] amino] -1- (3-amino-4-hydroxyphenyl) ethanol, N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1- hydroxyethyl] -2- (benzyloxy) phenyl] urea, N- [5- [2- [2- (9H-carbazol-2-yloxy) et.lamino] -1-hydroxyethyl] -2-hydroxyphenyljurea, N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2- (benzyloxy) phenyl] formamide, N '- [5- [2- [2- (9H- carbazol-2-yloxy) ethylamino] -1-hydro xiethyl] -2- (benzyloxy) phenyl] -N, N-dimethylsulfamide, N '- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] -N, N-dimethylsulfamide, 2- [N- [2- (9H-carbazol-2-yloxy) ethyl] amino] -1- [3- (methylamino) -4- (benzyloxy) phenyl] ethanol, 2- [ N- [2- (9H-carbazol-2-yloxy) ethyl] amino] -1- [3- (methylamino) -4-hydroxyphenyl-ethanol, N- [5- [2- [2- (9H-carbazole-2- iloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] -2-propanesulfonamide, 2- [N- [2- (9H-carbazol-2-yloxy) ethyl] amino] -1- (3-nitrophenyl) - ethanol, N'-fa-pp-IQH-carbazole ^ -ilox ethylamino-l-hydroxyethylpillill-NN-dimethylsulfamide, * 2- [N- [2- (9H-carbazol-2-yloxy) ethyl] amino] -1- (3-aminophenyl) ethanol,
W 2- [N- [2- (9H-carbazol-2-yloxy) ethyl] amino] -1- [3- (hydroxymethyl) -4- 10 hydroxyphenyl-ethanol, N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -3-hydroxyphenyl-methanesulfonamide, N- [3- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2- hydroxyphenyl-methanesulfonamide, 15 N- [3- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -4-hydroxyphenyl-methanesulfonamide, (R) N ' - [5- [2- [2- (9H-carbazol-2-yloxy) et.lamino] -1-hydroxyethyl] -2-hydroxyphenyl] -N, N-dimethylsulfamide, (S) N, - [5 - [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-20 hydroxyphenyl] -N, N-dimethylsulfamide, N- [3- [2- [2- (6- acetylamino-9H-carbazol-2-yloxy) ethylamino] -1- hydroxyethyl-phenyl-methanesulfonamide, N- [5- [2- [2- (6-acetylamino-9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] - 2-hydroxyphenyl] methanesulfonamide, (R) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-fluorophenyl-methanesulfonamide, (S) -N- [ 5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-fluorophenyl-methanesulfonamide, (R) -N- [5 - [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-chlorophenyl-methanesulfonamide, (S) -N- [5- [2- [2- (9H-carbazole- 2-yloxy) ethylamino] -1-hydroxyethyl] -2-chlorophenyl-methanesulfonamide, N, N-dimethyl- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] - 2-hydroxy-benzenesulfonamide, N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-iodophenyl-methanesulfonamide, N '- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-fluorophenyl] - N, N-dimethylsulfamide, N '- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino ] -1-hydroxyethyl] -2-chlorophenyl] -N, N-dimethylsulfamide, (R) -N-methyl- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl ] -2-hydroxy-benzenesulfone ida, (R) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2- (hydroxymethyl) phenyl] methanesulfonamide, (R) -N- [3- [2- [2- (Dibenzofuran-3-yloxy) ethylamino] -1-hydroxyethyl] -phenyl-methanesulfonamide, N '- [5- [2- [2- (dibenzofuran-3-ylox ) Ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] -N, N-dimethylsulfamide, (R) -N '- [5- [2- [2- (dibenzofuran-3-lox) i) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] -N, N-dimethylsulfamide, (S) -N '- [5- [2- [2- (dibenzofuran-3-yloxy) et.lamino] -1 -hydroxyethyl] -2-hydroxyphenyl] -N, N-dimethylsulfamide, N- [5- [2- [2- (dibenzofuran-3-yloxy] ethylamino] -1-hydroxyethyl] -2-fluorophenyl-methanesulfonamide, N- [5 - [2- [2- (Dibenzofuran-3-yloxy) ethylamino] -1-hydroxyethyl] -2-chlorophenyl-methanesulfonamide, N- [5- [2- [2- (d.benzothiophen-3-yloxy) ethylamino] -1 -hydroxyethyl] -2-hydroxyphenyl-methanesulfonamide, N '- [5- [2- [2- (dibenzothiophen-3-yloxy) ethylammonyl] -1-hydroxyethyl] -2-hydroxyphenyl] -N, N-dimethylsulfonamide, N- [3- [2- [2- (Dibenzothiophen-3-yloxy) ethylamino] -1-hydroxyethyl] phenyl] methanesulfonamide, (R) -N- [5- [2- [2- (dibenzothiophen-3-yloxy ) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl-methanesulfonamide, N- [5- [2- [2- (dibenzotophen-3-yloxy) ethalamino] -1-hydroxyethyl] -2 -fluorophenyl-methanesulfonamide, N- [5- [2- [2- (dibenzotophen-3-yloxy) ethylamino] -1-hydroxyethyl] -2- chlorophenyl-methanesulfonamide, ^ N- [5- [2- [2- ( 7-aminofluoren-2-yloxy) ethylamino] -1-hydroxyethyl] - 2- hydroxyphenyl-methanesulfonamide, 5 N '- [5- [2- [2- (7-acetylaminofluoren-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] -N, N-dimethylsulfamide, N' - [5 - [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-aminophenyl] -N-benzyl-N-methylsulfamide, r N- [5- [2- [2- ( 9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2- 10 aminophenyl-methanesulfonamide, N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2 - hydroxymethylphenyl-methanesulfonamide, N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-bromophenyl-methanesulfonamide, 15 N '- [5- [2- [ 2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl-2-hydroxyphenyl] -N-benzyl-N-methylsulfamide, N '- [5- [2- [2- (9H-carbazole-2- Loxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] - N, N-diethylsulfamide, N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-methoxyethyl ] -2- 20 aminophenylmethane sulfonamide, N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-methoxyethyl] -2-hydroxyphenyl-methanesulfonamide and N- [5- [2- [2- (dibenzothiophen-3-yloxy) ethylamino] -1-methoxyethylj-2-hydro xifeniljmetanosulfonamida. 2- [N- [2- (9H-carbazol-2-yloxy) ethyl] amino] -1- (4-hydroxyphenyl) ethanol, 2- [N- [2- (9H-carbazol-2-yloxy) ethyl] amino] -1- (2-fluorophenyl) ethanol, 2- [N- [2- (9H-carbazol-2-yloxy) ethyl] ] amino] -1- (2-hydroxyphenyl) ethanol, (R, R) -2- [N- [1- (9H-carbazol-2-yloxy) propan-2-yl] amino] -1-phenyl ] ethanol, 2- [N- [2- (9H-carbazol-2-yloxy) ethyl] amino] -1-phenyl] ethanol, (R) - [2- [N- [2- (9H-carbazole-2 -yloxy) ethyl] amino] -1-phenyl] ethanol, (S) - [2- [N- [2- (9H-carbazol-2-yloxy) ethyl] amino] -1-phenyl] ethanol, [2- [N- [2- (3-acetylamino-9H-carbazol-2-yloxy) ethyl] amino] -1-phenyl-ethanol, [2- [N- [2- (3-amino-9H-carbazol-2-yloxy)] ethyl] amino] -1-phenyl] ethanol, [2- [N- [2- (3-hydroxy-9H-carbazol-2-yloxy) ethyl] amino] -1-phenyl] ethanol, [2- [N- [2- (6-amino-9H-carbazol-2-yloxy) ethyl] amino] -1-phenol] ethanol, [2- [N- [2- (6-acetylamino-9H-carbazol-2-yloxy] ) ethyl] amino] -1-phenyl] ethanol, [2- [N- [1 - (9H-carbazol-2-yloxy) propan-2-yl] amino] -1-phenyl-ethanol and [2- [N- [ 2- (dibenzofuran-3-yloxy) ethyl] amino] -1-phenyl] ethanol. N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-methoxyethyl] -2-hydroxyphenyl-methanesulfonamide, N- [5- [2- [2- (dibenzothiophen-3-yloxy) ethylamino] -1-methoxyethyl] -2-hydroxyphenyl-methanesulfonamide, N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-methoxyethyl] -2-aminophenyl-methanesulfonamide and N- [5 - [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-methoxyethyl] -2-chlorophenyl-methanesulfonamide; or a salt of them. Other suitable beta agonists include the compounds of the U.S. patent. No. 5786356 and published European patent application No. EP 764640A, especially the specific examples including LY-377604. Suitable beta agonists further include the compounds of WO 9616938 and EP 801059, especially the specific examples which include 2- [3- (7-carboxymethoxy-indol-3-yl) - (2R) -2-propylamino] - (1 R) -1- (3-chlorophenyl) ethanol (AD-9677) and derivatives thereof. The descriptions of each of these documents are incorporated herein by reference, with particular reference to the preparation methods and pharmaceutically acceptable derivatives of the compounds. With reference to EP 801059, the particular beta agonists included herein are those selected from the list consisting of: 2- [3- (7-methoxyindol-3-yl) -2-propylamino] -1- (3-chlorophenyl) )ethanol; 2- [3- (7-ethoxyindol-3-yl) -2-propylamino] -1- (3-chlorophenyl) ethanol; 2- [3- (7-methoxycarbonylmethoxyindol-3-yl) -2-propylamine] -1- (3-chlorophenyl) ethanol; 2- [3- (7-carboxymethoxyindol-3-yl) -2-propylamino] -1- (3-chlorophenyl) ethanol; and derivatives thereof. It will be understood that the beta agonist and the other antidiabetic agent are each administered in a pharmaceutically acceptable form, including pharmaceutically acceptable derivatives such as pharmaceutically acceptable salts, esters and solvates thereof, according to the relevant pharmaceutically active agent. In certain cases, the names used for the other antidiabetic agent can be referred to a particular pharmaceutical form of the relevant active agent: It will be understood that all pharmaceutically acceptable forms of the active agents per se are contemplated by this invention. Suitable pharmaceutically acceptable forms of the other antidiabetic agent depend on the particular agent that is used, but include known pharmaceutically acceptable forms of the particular agent selected. Such derivatives are found or referred to in standard reference texts such as British and EU Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example see edition 31 page 341 and pages cited there) or the publications mentioned above. Suitable pharmaceutically acceptable forms of the beta agonist of formula (I), which include salt forms and solvate forms, include those described in WO97 / 25311 and EP0882707A1. The beta agonist is prepared according to published methods, for example when the beta agonist is a compound of formula (I) of WO97 / 25311 and EP0882707AI, or a derivative thereof such as a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of it, then it is prepared according to the methods described there.
Some of the compounds mentioned therein, for example the beta agonists of WO97 / 25311, EP0882707AI, USP5786356, EP764640A, WO9616938 and EP801059 and the thiazolidinediones, may contain one or more chemical carbon atoms and therefore, may exist in two or more isomeric forms, which are contemplated by the invention, either as individual isomers or as mixtures of isomers, including racemates. Some of the compounds mentioned therein, in particular the thiazolidinediones such as compound (I), can exist in one of different tautomeric forms, which are contemplated by the invention as individual tautomeric forms or as mixtures thereof. The beta agonist and the other antidiabetic agent of choice are prepared according to known methods, such methods are found or referred to in standard reference texts such as British and EU Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example, see edition 31 page 341 and pages cited there) or the publications mentioned above. When used herein, the term "conditions associated with diabetes" includes those conditions associated with the prediabetic condition, conditions associated with the same diabetes mellitus, and complications associated with diabetes mellitus. When used herein, the term "conditions associated with the prediabetic state" includes conditions such as insulin resistance, which includes hereditary insulin resistance, impaired glucose tolerance and hyperinsulinemia. "Conditions associated with diabetes mellitus itself" include hyperglycemia, insulin resistance, which includes resistance to acquired insulin and obesity. Additional conditions associated with diabetes mellitus itself include hypertension and cardiovascular disease, especially atherosclerosis and conditions associated with insulin resistance. Conditions associated with insulin resistance include polycystic ovary syndrome and steroid-induced insulin resistance and gestational diabetes. "Complications associated with diabetes mellitus" includes kidney disorder, especially kidney disorder associated with type 2 diabetes, neuropathy and retinopathy. Renal disorders associated with Type 2 diabetes include nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis, and end-stage renal disease. As used herein, the term "pharmaceutically acceptable" encompasses both human and veterinary use: for example, the term "pharmaceutically acceptable" encompasses a compound acceptable from the veterinary point of view. Preferably, diabetes mellitus is Type 2 diabetes. Suitably, the particularly beneficial effect on glycemic control provided by the treatment of the invention is an improved therapeutic ratio for the combination of the invention with respect to the therapeutic ratio for a compound of the combination when used alone and in a dose that provides equivalent efficacy for the combination of the invention. In a preferred aspect, the particularly beneficial effect of the glycemic control provided by the treatment of the invention is indicated as a synergistic effect in relation to the expected control of the effects of the individual active agents. In another aspect of the invention, the dose combination of the beta agonist and the other agent will produce a greater beneficial effect than can be achieved for any agent only at a dose twice that used for that agent in the combination. The glycemic control can be characterized using conventional methods, for example by measuring an index typically used for glycemic control, such as fasting plasma glucose or glycosylated hemoglobin (Hb A1c). Such indices are determined using standard methodology, for example that described in: Tuescher A, Richterich, P., Schweix. Med. Wschr. 101 (1971), 345 and 390 and Frank P., Monitoring the Diabetic Patent with Glycosolated Hemoglobin Measurements', Clinical Products 1988. In a preferred aspect, the dosage level of each of the active agents when used in accordance with the treatment of the invention,. it will be less than what would have been required from a purely additive effect with glycemic control.
It is also considered that the treatment of the invention will effect an improvement, in relation to the individual agents, in the levels of advanced glycation end products (AGE), and serum lipids that include total cholesterol, HDL-cholesterol, LDL-cholesterol that it includes improvements in the relationships thereof, in particular, an improvement in serum lipids that include total cholesterol, HDL-cholesterol, LDL-cholesterol including improvements in their ratios. As indicated above, it is also considered that treatment with the combination of the beta agonist and the other antidiabetic agents (especially sulfonylureas, insulin sensitizers or insulin) will significantly reduce, preferably remove, the effects that increase the body weight of the other antidiabetic agents. It is considered that the thermogenic effects of the beta 3 agonist will increase in the combination treatment of the invention. Thus, for example, the weight-reducing effects of the beta 3 agonist will be extended in the combination treatment of the invention. In the treatment of the invention, the active medicaments are preferably administered in the form of a pharmaceutical composition. As mentioned above, such compositions may include both medicaments or only one of the medicaments. Accordingly, in one aspect, the present invention further provides a pharmaceutical composition comprising a beta agonist and another antidiabetic agent and a pharmaceutically acceptable carrier therefor.
Thus, in a further aspect, the invention also provides a method for making a pharmaceutical composition comprising a beta agonist, another antidiabetic agent and a pharmaceutically acceptable carrier therefor, which process comprises mixing the beta agonist, another antidiabetic agent and a pharmaceutically acceptable vehicle. Preferably, the compositions are in a unit dose form in an amount suitable for the relevant daily dosage. Suitable dosages, especially including unit dosages, of the beta agonist or the other antidiabetic agent, include known dosages including unit doses for these compounds as described or referred to in the reference text such as British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example, see edition 31 page 341 and pages cited there) or the publications mentioned above. Thus, suitable dosages for the beta agonists of WO97 / 25311 and EP0882707A1 include those described therein, for example 0.01 to 2000 mg per day. In addition, the appropriate dose of the other beta agonists mentioned herein, include those mentioned in the relevant publications mentioned above, for example suitable AD-9677 doses include those described in WO 9616938 and EP 801059, such as in the 0.01 scale -20 mg / kg / day including 0.05-10 mg / kg / day.
For the alpha glucosidase inhibitor, an adequate amount of acarbose is in the range of 25 to 600 mg, including 50 to 600 mg, for example 100 mg or 200 mg. For biguanide, a suitable dosage of metformin is between 100 to 3000 mg, for example 250, 500 mg, 850 mg or 1000 mg. For the insulin secretagogue, an adequate amount of glibenclamide is in the range of 2.5 to 20 mg, for example 10 mg or 20 mg; an adequate amount of glipizide is in the range of 2.5 to 40 mg; an adequate amount of gliclazide is in the range of 40 to 320 mg; an adequate amount of tolazamide is in the range of 100 to 1000 mg; an adequate amount of toibutamide is in the range of 1000 to 3000 mg; an adequate amount of chlorpropamide is in the range of 100 to 500 mg; and an adequate amount of gliquidone is on the scale of 15 to 180 mg. In addition, an adequate amount of glimepiride is 1 to 6 mg and an adequate amount of glipentide is 2.5 to 20 mg. An adequate amount of repaglinide is in the range of 0.5 mg to 20 mg, for example 16 mg. In addition, an adequate amount of nateglinide is
90 to 360 mg, for example 270 mg. In a particular aspect, the composition comprises 2 to 12 mg of the compound (I). Suitably, the composition comprises 2, 3, 4, 5, 6, 7, 8,
9, 10, 11 or 12 mg of the compound (I). Particularly, the composition comprises 2, a 4, 4 to 8 or 8 to 12 mg of the compound (I).
Particularly, the composition comprises 2 to 4 mg of the compound
(I) - Particularly, the composition comprises 4 to 8 mg of the compound
(- Particularly, the composition comprises 8 to 12 mg of compound (I) Preferably, the composition comprises 2 mg of compound (I) Preferably, the composition comprises 4 mg of compound (I) Preferably, the composition comprises 8 mg of the compound (I) Suitable unit dosages of other insulin sensitizers include 100 to 800 mg of troglitazone such as 200, 400, 600 or 800 or 5 to 50 mg, including 10 to 40 mg, of pioglitazone, such as 20, 30 or 40 mg, and also include 15, 30 and 45 mg of pioglitazone In the treatment, the drugs can be administered from 1 to 6 times a day, but preferably 1 or 2 times a day. of each particular active agent in any given composition may vary, as required, within a range of known doses to be required with respect to the accepted dosage regimens for that compound. n can be adapted as required to consider the advantageous effects of combining the agents as mentioned herein. It will be understood that the beta agonist and the other antidiabetic agent are in a pharmaceutically acceptable form, including pharmaceutically acceptable derivatives such as pharmaceutically acceptable salts, esters and solvates thereof, as appropriate for the pharmaceutically active agent of choice. In certain cases, the names used for the antidiabetic agent may be related to a particular pharmaceutical form of the relevant relative active agent: It will be understood that all pharmaceutically acceptable forms of the active agents per se are contemplated by the invention. The present invention also provides a pharmaceutical composition comprising a beta agonist, another antidiabetic agent and a pharmaceutically acceptable carrier therefor, for use as an active therapeutic substance. In particular, the present invention provides a pharmaceutical composition comprising a beta agonist, another antidiabetic agent and a pharmaceutically acceptable carrier therefor, for use in the treatment of diabetes mellitus, especially type 2 diabetes and conditions associated with diabetes mellitus. Typically, the compositions are adapted for oral administration. However, they can be adapted for other modes of administration, for example parenteral administration, sublingual or transdermal administration. The compositions may be in the form of tablets, capsules, powders, granules, troches, suppositories, reconstitutable powders or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
In order to obtain administration consistency, it is preferred that a composition of the invention be in the form of a unit dose. The unit dosage presentation forms for oral administration may be in tablet or capsule and may contain as necessary, conventional excipients such as binding agents, fillers, lubricants, glidants, disintegrants and wetting agents. Solid oral compositions can be prepared by conventional mixing, filling or tabletting methods. The repeated mixing operations can be used to distribute the active agent through those compositions using large amounts of fillers. Such operations, of course, are conventional in the art. The tablets can be coated according to known methods in normal pharmaceutical practice, in particular with an enteric coating. Oral liquid preparations may be in the form of, for example, emulsions, syrups or elixirs or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, hydrogenated edible fats.; emulsifying agents, for example, lecithin, sorbitan monooleate, acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oil esters such as glycerin esters, propylene glycol or ethyl alcohol;
preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired, conventional flavoring or coloring agents. For parenteral administration, the unit dosage forms of fluid are prepared using the compound and a sterile vehicle, and depending on the concentration used, they can either be suspended or dissolved in the vehicle. When preparing solutions, the compound can be dissolved in water for injection and can be sterilized by filter before being poured into a suitable vial or flask and sealed. Advantageously, adjuvants such as a local anesthetic, a preservative and pH regulating agent can be dissolved in the vehicle. To improve stability, the composition can be frozen after being poured into the bottle and the water can be removed under vacuum. Parenteral suspensions are prepared substantially equally, except that the active compound is suspended in the vehicle instead of being dissolved, and sterilization can not be performed through filtration. The compound can be sterilized by exposure to ethylene oxide before suspension in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound. The compositions may contain from 0.1 to 99% by weight, preferably 10-60% by weight, of the active material, depending on the method of administration. Examples of binding agents include acacia, alginic acid, calcium carboxymethylcellulose, sodium carboxymethylcellulose, dextrates, dextrin, dextrose, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, polyvinylpyrrolidone, pregelatinized starch, sodium alginate, sorbitol, starch, syrup, tragacanth. Examples of fillers include calcium carbonate, calcium sulfate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, compressible sugar, sugar for confectionery, dextrates, dextrin, dextrose, calcium phosphate dibasic dihydrate, calcium phosphate dibasic, fructose, palmito-stearate glyceryl, glycine, hydrogenated vegetable oil type 1, kaolin, lactose, corn starch, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, polymethacrylates, potassium chloride, cellulose powder, pregelatinized starch, sodium chloride, sorbitol, starch, sucrose, sugar spheres, talc, tribasic calcium phosphate, xylitol. Examples of lubricants include calcium stearate, glyceryl monostearate, glyceryl palmito stearate, magnesium stearate, microcrystalline cellulose, sodium benzoate, sodium chloride, sodium lauryl sulfate, stearic acid, sodium stearyl fumarate, talc, zinc stearate. Examples of glidants include colloidal silicon dioxide, powdered cellulose, magnesium trisilicate, silicon dioxide, talc. Examples of disintegrants include alginic acid, calcium carboxymethylcellulose, sodium carboxymethylcellulose, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminum silicate, microcrystalline cellulose, methylcellulose, polyvinylpyrrolidone, potassium polacrilin, pregelatinized starch, sodium alginate, sodium lauryl sulfate, sodium starch glycolate. An example of a pharmaceutically acceptable wetting agent is sodium lauryl sulfate. The compositions are prepared and formulated according to conventional methods, such as those described in standard reference texts, for example British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (see for example the edition 31 page 341 and pages there cited) and Harry's Cosmeticology (Leonard Hill Books) or the aforementioned publications. For example, the solid oral compositions can be prepared by conventional mixing, filling or tabletting methods. Repeated mixing operations can be used to distribute the active agent through the compositions using large amounts of fillers. Such operations, of course, are conventional in the art. The tablets can be coated according to known methods in normal pharmaceutical practice. If desired, the compositions may be in the form of a package accompanied by written or printed instructions for use. Adverse toxicological effects of the compositions or methods of the invention are not expected in the aforementioned dosage scales.
Claims (18)
1. The use of a beta agonist in combination with another antidiabetic agent for the preparation of a medicament for the treatment of diabetes mellitus and conditions associated with diabetes mellitus in a mammal such as a human.
2. The use as claimed in claim 1, wherein the other antidiabetic agent is selected from an alpha glucosidase inhibitor, a biguanide, an insulin secretagogue, an insulin sensitizer and insulin.
3. The use as claimed in claim 1 or claim 2, wherein the other antidiabetic agent is an alpha glucosidase inhibitor.
4. The use as claimed in claim 3, wherein the alpha glucosidase inhibitor is selected from acarbose, emiglitate, miglitol and voglibose.
5. The use as claimed in claim 1 or claim 2, wherein the other antidiabetic agent is a biguanide.
6. The use as claimed in claim 5, wherein the biguanide is selected from metformin, buformin and phenformin.
7. - The use as claimed in claim 1 or claim 2, wherein the other antidiabetic agent is an insulin secretagogue.
8. The use as claimed in claim 7, wherein the insulin secretagogue is a sulfonylurea.
9. The use as claimed in claim 7 or claim 8, wherein the sulfonylurea is selected from glibenclamide, glipizide, gliclazide, glimepiride, tolazamide, toibutamide, acetohexamide, carbutamide, chlorpropamide, glibornuride, gliquidone, glisentide, glisolamide , glisoxepide, glyclopramide, glycylamide and glipentide.
10. The use as claimed in claim 1 or claim 2, wherein the other antidiabetic agent is an insulin sensitizer.
11. The use as claimed in claim 10, wherein the insulin sensitizer is the compound (I) or a derivative thereof.
12. The use as claimed in claim 10 or 11, wherein the insulin sensitizer is the compound (I) or a derivative thereof.
13. The use as claimed in claim 10 or 11, wherein the insulin sensitizer is (+) - 5 - [[4 - [(3,4-dihydro-6-hydroxy-2.5, 7,8-tetramethyl-2H-1-benzopyran-2-yl) methoxy] phenyl] methyl] -2,4-thiazolidinedione (or troglitazone), 5- [4 - [(1-methylcyclohexyl) methoxy] benzyl] thiazolidine-2,4-dione (or ciglitazone), 5- [4- [2- (5-ethylpyridin-2-yl) ethoxy] benzyl] thiazolidin-2,4-dione ( or pioglitazone) or 5 - [(2-benzyl-2,3-dihydrobenzopyran) -5-ylmethyl) thiazolidine-2,4-dione (or englitazone).
14. The use as claimed in any of claims 1 to 13, wherein the beta agonist is a compound of formula (I) of WO / 9725311.
15. The use as claimed in any of claims 1 to 14, wherein the beta agonist is selected from the list consisting of examples of WO / 9725311.
16. A pharmaceutical composition comprising a beta agonist and another antidiabetic agent and a pharmaceutically acceptable carrier therefor.
17. The composition according to claim 16, further characterized in that the other antidiabetic agent is selected from an alpha glucosidase inhibitor, a biguanide, an insulin secretagogue or an insulin sensitizer.
18. The composition according to claim 17, in unit dosage form.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9824789.3 | 1998-11-11 | ||
| GB9824790.1 | 1998-11-11 | ||
| GB9824791.9 | 1998-11-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA01004826A true MXPA01004826A (en) | 2002-06-05 |
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