CN1281359A - Use of thiazolidinediones for treatment of hyperglycaemia - Google Patents

Use of thiazolidinediones for treatment of hyperglycaemia Download PDF

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Publication number
CN1281359A
CN1281359A CN98812083A CN98812083A CN1281359A CN 1281359 A CN1281359 A CN 1281359A CN 98812083 A CN98812083 A CN 98812083A CN 98812083 A CN98812083 A CN 98812083A CN 1281359 A CN1281359 A CN 1281359A
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hyperglycemia
insulin sensitizers
plasma glucose
chemical compound
pharmaceutically
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CN98812083A
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Chinese (zh)
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R·E·白金汉
S·A·史密斯
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SmithKline Beecham Ltd
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SmithKline Beecham Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

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  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Diabetes (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Hematology (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Obesity (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Thiazole And Isothizaole Compounds (AREA)

Abstract

A method for the treatment of hyperglycaemia wherein plasma glucose levels are in the range of elevated normal to </=126mg/dl, which method comprises administering an effective non-toxic and pharmaceutically acceptable amount of an insulin sensitiser, to a mammal in need thereof.

Description

Use the thiazolidinedione treatment hyperglycemia
The present invention relates to a kind of Therapeutic Method of novelty, particularly relate to a kind of method that is used for the treatment of and/or prevents certain specific hyperglycemia.
European patent application published numbers 0,306,228 relates to some tetrahydrothiazole diketone derivatives, has disclosed them and has had the activity of blood sugar lowering and blood fat reducing.A disclosed concrete thiazolidinedione is 5-[4-[2-(N-methyl-N-(2-pyridine radicals) amino) ethyoxyl in EP 0306228] benzyl] thiazolidine-2,4-diketone (after this being called ' chemical compound (I) ').WO 94/05659 discloses some salt of chemical compound (I), comprises maleate.
Chemical compound (I) is the example that a class is called as the anti--hyperglycemia agent of ' insulin sensitizers ' (or ' insulin action reinforcing agent ').Particularly, chemical compound (I) is a thiazolidinediones insulin sensitizers.
European patent application published number: 0008203,0139421,0032128,0428312,0489663,0155845,0257781,0208420,0177353,0319189,0332331,0332332,0528734,0508740; International application published number 92/18501,93/02079,93/22445 and U.S. Patent number 5104888 and 5478852 also disclose some thiazolidinediones insulin sensitizers.
It is generally acknowledged to have active another group chemical compound of insulin sensitizers, is to be the chemical compound of representative with disclosed chemical compound in international application published WO93/21166 and WO94/01420.These chemical compounds are called " acyclic insulin sensitizers " at this.Other example of acyclic insulin sensitizers is a disclosed chemical compound in U.S. Patent number 5232945 and international application published WO92/03425 and WO91/19702.
Some other example of insulin sensitizers is in European patent application published number 0533933, disclosed chemical compound in Japan patent applicant announce number 05271204 and the U.S. Patent number 5264451.
According to Report of the Expert Committee of the Diagnosis andClassification of Diabetes Mellitus (Diabetes Care, vol 20 (7), 1997,1183-1197) described, the feature of type 2 diabetes mellitus is fasting glucose glucose level 〉=126mg/dl (be defined as at least 8 hours on an empty stomach at this and do not take in heat).This report has also been described diabetes and normally how have been developed in the time in several years, rise to feature with the fasting blood sugar level that purifies the blood, rise to the distinctive hyperglycemia state of described obvious type 2 diabetes mellitus always from being considered to normal plasma glucose levels (approximately 110mg/dl).This report points out that also the metabolism state of transition comprises between normal glucose homoiostasis and diabetes, impaired glucose dosis tolerata and impaired fasting glucose level.
Know that from EP0306228 Compound I can be used for preventing hyperglycemia, therefore can be used for treating impaired glucose dosis tolerata.International application published WO95/07694 points out openly that also thiazolidinediones can be used for treating impaired glucose dosis tolerata, thereby prevents or delay the outbreak of type 2 diabetes mellitus.But EP0306228 and WO95/07694 do not mention the treatment to any particular glucose scope.
Show that chemical compound (I) can provide particularly advantageous effect to Blood glucose control from being higher than normal level to the hyperglycemia scope of≤126mg/dl, thereby delay or prevent that hyperglycemia from further raising.
Therefore, the invention provides a kind of hyperglycemia that is used for the treatment of, the method of hyperglycemia on an empty stomach particularly, wherein plasma glucose levels is being higher than normal value to the scope of≤126mg/dl, and this method comprises to the administration of needs effectively and the avirulence and the insulin sensitizers of suitable dose pharmaceutically.
Therefore, the invention provides a kind of being used for hyperglycemia, be the method that the patient of feature improves glycemic control particularly with the empty stomach hyperglycemia, improvement described here is to provide under the state of hyperglycemia, wherein plasma glucose levels is to be higher than normal value to the scope of≤126mg/dl, thereby delay or prevent that hyperglycemia from further raising, this method comprises to the administration of needs effectively and the avirulence and the insulin sensitizers of suitable dose pharmaceutically.
On the other hand, the invention provides a kind of prevention hyperglycemia, the method of hyperglycemia on an empty stomach particularly, here plasma glucose levels is in the scope of＞126mg/dl, and this method comprises to the administration of needs effectively and the avirulence and the insulin sensitizers of suitable dose pharmaceutically.
Stipulated a kind of special patient's condition at this: be higher than the empty stomach hyperglycemia feature of normal value to the≤126mg/dl scope except having plasma glucose levels, also having in the hyperglycemia of plasma glucose levels after the test of oral glucose tolerance amount in＜140mg/dl scope.
Also stipulated the another kind of patient's condition at this, be higher than normal value to the≤126mg/dl scope on an empty stomach the hyperglycemia feature except having, also having in plasma glucose levels after the test of oral glucose tolerance amount in 140 hyperglycemias to the＜200mg/dl scope.
Suitable insulin sensitizers is the thiazolidinediones insulin sensitizers.
Suitable thiazolidinediones insulin sensitizers is chemical compound (I), perhaps its tautomeric form, perhaps their pharmaceutically suitable salt, or its pharmaceutically suitable solvate.
Other thiazolidinediones insulin sensitizers that is fit to comprises, (+)-5-[[4-[(3,4-dihydro-6-hydroxyl-2,5,7,8-tetramethyl-2H-1-.alpha.-5:6-benzopyran-2-yl) methoxyl group] phenyl] methyl]-2,4-thiazolidinedione (or troglitazone), the 5-[4-[(1-methylcyclohexyl) methoxyl group] benzyl] thiazolidine-2,4-diketone (or ciglitazone), 5-[4-[2-(5-ethylpyridine-2-yl) ethyoxyl] benzyl] thiazolidine-2,4-diketone (or pioglitazone), or 5-[(2-benzyl-2, the 3-dihydrobenzopyrans)-the 5-ylmethyl) thiazolidine-2,4-diketone (or englitazone).
One concrete aspect, this method comprises and gives 2-12mg chemical compound (I), particularly by administration every day.
Especially, this method comprises and gives 2-4 every day, 4-8, or 8-12mg chemical compound (I).
Especially, this method comprises and gives 2-4mg chemical compound (I), particularly by administration every day.
Especially, this method comprises and gives 4-8mg chemical compound (I), for example greater than 4mg such as 4.1mg to 8mg, particularly by administration every day.
Especially, this method comprises and gives 8-12mg chemical compound (I), particularly by administration every day.
Preferably, this method comprises and gives 2mg chemical compound (I), particularly by administration every day.
Preferably, this method comprises and gives 4mg chemical compound (I), particularly by administration every day.
Preferably, this method comprises and gives 8mg chemical compound (I), particularly by administration every day.
Should be understood that insulin sensitizers such as chemical compound (I) are the form administrations that is suitable for pharmaceutically,, comprise giving pharmaceutically suitable derivant such as its salt, ester and solvate that pharmaceutically is suitable for if suitable.
The salt form that pharmaceutically is suitable for that insulin sensitizers such as chemical compound (I) are suitable is included in the form of aforementioned patent and patent application such as EP 0306228 chemical compound (I) salt described in WO 94/05659.
For the preferred salt that pharmaceutically is suitable for of chemical compound (I) is maleate.
The solvated compounds form that pharmaceutically is suitable for that insulin sensitizers such as chemical compound (I) are suitable, be included in the aforementioned patent and patent application such as EP 0306228 and WO 94/05659 described in the solvate forms, particularly hydrate of chemical compound (I).
Available known method prepares insulin sensitizers such as chemical compound (I), or its salt that pharmaceutically is suitable for, perhaps its solvate that pharmaceutically is suitable for, and these methods for example are included among aforementioned patent and patent application such as EP 0306228 and the WO 94/05659.At this disclosure described in aforementioned patent and patent application such as EP 0306228 and the WO 94/05659 is incorporated herein by reference.
Thiazolidinediones insulin sensitizers such as chemical compound (I), a kind of form in can several tautomeric forms exists, and the application comprises all tautomeric forms or as single tautomeric forms, perhaps as their mixture.Some insulin sensitizers such as chemical compound (I) comprise one or several chiral carbon atom, therefore, can exist with two kinds or several stereoisomer form: all forms include in this application, perhaps, perhaps, comprise racemic modification as their mixture as single isomer.
Term " pharmaceutically is suitable for " as used herein, comprises that human and veterinary use: for example term " pharmaceutically is suitable for " and comprises that the veterinary goes up compounds suitable for use.
The test of oral glucose tolerance amount is with reference to Diabetes Care.vol 20 (7), 1997, the test among the 1183-1197 as used herein.
Hyperglycemia is taked the general implication of understanding in this area " to be higher than normal value " as used herein, reference example such as Report Expert of the Committee of the Diagnosis andClassification of Diabetes Mellitus, but mean the wherein blood glucose of plasma glucose levels＞110mg/dl usually.
In the methods of the invention, preferably give active drug with the form of Pharmaceutical composition.Point out that as top this based composition can comprise two kinds of medicines or only a kind of medicine.
Can prepare this based composition by a kind of insulin sensitizers such as chemical compound (I) (particularly 2-12mg) are mixed with a kind of carrier that pharmaceutically is suitable for.
This based composition is generally suitable for oral administration.But they also may be suitable for other administering mode, for example drug administration by injection, Sublingual or transdermal administration.
Described compositions can be a tablet, capsule, powder, granule, lozenge, suppository, powder formulated agent again, perhaps liquid preparation such as oral solution or aseptic injectable solution agent or suspendible liquor.
In order to reach the concordance of administration, preferably making compositions of the present invention is the form of unit dose.
Representative form for the oral administration unit dose can be tablet and capsule, and can contain conventional excipient, for example binding agent such as syrup, arabic gum, gelatin, sorbitol, tragakanta, or polyvinylpyrrolidone; Filler such as lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; Film-making lubricant such as magnesium stearate; Disintegrating agent such as starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline Cellulose; Perhaps pharmaceutically suitable wetting agent such as sodium lauryl sulfate.
Preferred said composition is the unit dosage form that is suitable for corresponding every day of dosage.
The dosage that is fit to for this insulin sensitizers is included in disclosed dosage in above-mentioned patent and the patent application.
The suitable dose of chemical compound (I) that comprises unit dose is for containing 1,2,3,4,5,6,7,8,9,10,11, or 12mg chemical compound (I).
In the treatment that comprises the chemical compound different with chemical compound (I), the usually existing narration in the above-mentioned patent that is cited as a reference of required dosage and prescription: example comprises and gives 200-800mg (for example 200,300 or 400mg) troglitazone.
In treatment, can give this medicine 1-6 time every day, but every day 1 time or 2 times most preferably.
Solid oral composition can be by conventional mixing, and filling or tabletting method prepare.Married operation that can be by repeatedly is so that be evenly dispersed in the compositions of using a large amount of filleies active drug.Certainly this this area that operates in is conventional.Can be according to known method in the pharmacy practice of routine to this tablet coating, particularly enteric coating.
Oral liquid can be, example emulsion, and the form of syrup or elixir is a dry products perhaps, is used for being mixed with liquid again with water or other excipient that is fit to before usefulness.This liquid preparation can also comprise some conventional additives, for example suspending agent such as sorbitol, syrup, methylcellulose, gelatin, hydroxyethyl-cellulose, carboxymethyl cellulose, aluminium stearate gel, hydrogenant edible fat; Emulsifying agent such as lecithin, Arlacel-80, or arabic gum; Non-water excipient (can comprise edible oil) is as almond oil, fractionated Oleum Cocois, grease such as glyceride, propylene glycol or ethanol; Antiseptic such as methyl or propyl group be right-hydroxybenzoate or sorbic acid; And the aromatic or the coloring agent that also can comprise routine if desired.
For drug administration by injection, use chemical compound of the present invention and aseptic excipient to can be made into the liquid form of unit dose, and, depending on employed concentration, this chemical compound can suspend or be dissolved in the excipient.When the preparation solution, can be with the The compounds of this invention injection of making soluble in water, degerming after filtration before pack into suitable phial or ampoule, sealing then.Dissolve in some adjuvants such as local anesthetic in excipient, antiseptic and buffer agent are useful.In order to increase stability, can after the phial of packing into, make compositions freezing, and under vacuum, remove moisture.Can prepare the injection suspension agent by substantially the same mode, different is, chemical compound (I) is to be suspended in the excipient rather than to be dissolved in wherein, therefore can not be by means of the Filtration degerming.Can before being suspended in aseptic excipient, make this chemical compound sterilization with oxirane.In this compositions, add surfactant or wetting agent, so that advantageously impel chemical compound to distribute equably.
Depend on medication, compositions can contain the effective ingredient of 0.1%-99% weight, preferably contains the effective ingredient of 10%-60% weight.
If desired, compositions can be with the packaged form of literal operation instructions.
Can be according to the conventional method preparation and the preparation present composition, for example can be according to the canonical reference textbook, as Britain and American Pharmacopeia, Remington ' s Pharmaceutical Sciences (Mack Publishing Co.), disclosed method preparation and preparation among Martindale The Extra Pharmacopoeia (London, pharmacy publishing house) and Harry ' the s Cosmeticology (Leonard HillBooks).
Therefore, the invention provides and use insulin sensitizers such as chemical compound (I) (particularly 2-12mg) manufacturing medicine, be used for the treatment of hyperglycemia, particularly wherein plasma glucose levels is being higher than the empty stomach hyperglycemia patient of normal value to the≤126mg/dl scope.
The present invention also provides application insulin sensitizers such as chemical compound (I) (particularly 2-12mg) to make medicine, be used for improving with hyperglycemia, it particularly is the glycemic control of feature with the empty stomach hyperglycemia, the improvement that is provided is that patient's plasma glucose levels is being higher than the hyperglycemia of normal value to the≤126mg/dl scope, thereby delays or prevent that hyperglycemia from further raising.
Be on the other hand in addition, the invention provides and use insulin sensitizers such as chemical compound (I) (particularly 2-12mg) manufacturing medicine, be used to prevent the wherein hyperglycemia of plasma glucose levels＞126mg/dl, particularly the empty stomach hyperglycemia.
Particularly, the invention provides contain insulin sensitizers such as chemical compound (I) (particularly 2-12mg) with and the Pharmaceutical composition of suitable carrier pharmaceutically, be used for the treatment of hyperglycemia, hyperglycemia on an empty stomach particularly, wherein plasma glucose levels is being higher than normal value to the scope of≤126mg/dl, perhaps be used to improve with the empty stomach hyperglycemia is the glycemic control of feature, the improvement that is provided is that patient's plasma glucose levels is being higher than the hyperglycemia of normal value to the scope of＜126mg/dl, thereby delay or prevent that hyperglycemia from further raising, perhaps this compositions also can be used for preventing the wherein hyperglycemia of plasma glucose levels＞126mg/dl, particularly the empty stomach hyperglycemia.
For compositions of the present invention or the inventive method, expection is without any toxic and side effects in above-mentioned dosage range.

Claims (12)

1. one kind is used for the treatment of plasma glucose levels wherein in the method that is higher than the hyperglycemia of normal value to the≤126mg/dl scope, and this method comprises to the administration of needs treatment effectively and the avirulence and the insulin sensitizers of suitable dose pharmaceutically.
2. the process of claim 1 wherein that hyperglycemia is the empty stomach hyperglycemia.
3. the method for claim 2, wherein the characteristics of this hyperglycemia are, the fasting plasma glucose level is being higher than normal value to≤126 mg/dl scopes, and another characteristics are hyperglycemia to occur after the test of oral glucose tolerance amount, wherein plasma glucose levels＜140mg/dl.
4. the method for claim 2, wherein the characteristics of this hyperglycemia are, the fasting plasma glucose level is being higher than normal value to≤126mg/dl scope, another characteristics are hyperglycemia to occur after the oral glucose tolerance amount test, wherein plasma glucose levels 140 to＜200mg/dl scope.
5. one of any method among the claim 1-4, wherein insulin sensitizers is the thiazolidinediones insulin sensitizers.
6. one of any method among the claim 1-5, wherein insulin sensitizers is chemical compound (I)
7。The method of claim 6 wherein gives 2-12mg chemical compound (I) every day.
8. one of any method among the claim 1-4, wherein insulin sensitizers is to be selected from: (+)-5-[[4-[(3,4-dihydro-6-hydroxyl-2,5,7,8-tetramethyl-2H-1-.alpha.-5:6-benzopyran-2-yl) methoxyl group] phenyl] methyl]-2,4-thiazolidinedione (or troglitazone), the 5-[4-[(1-methylcyclohexyl) methoxyl group] benzyl] thiazolidine-2,4-diketone (or ciglitazone), 5-[4-[2-(5-ethylpyridine-2-yl) ethyoxyl] benzyl] thiazolidine-2,4-diketone (or pioglitazone), and 5-[(2-benzyl-2, the 3-dihydrobenzopyrans)-and the 5-ylmethyl) thiazolidine-2,4-diketone (or englitazone), perhaps their tautomeric forms, the salt of Shi Yonging pharmaceutically, the perhaps solvate that pharmaceutically is suitable for.
9. one of any method among the claim 1-8, wherein insulin sensitizers is to be suitable for the liquid preparations for oral administration form.
10. the method for claim 9, wherein compositions is the form of unit dose.
11. insulin sensitizers is used for the treatment of application in the medicine of hyperglycemia in preparation, plasma glucose levels is being higher than normal value to≤126mg/dl scope in the wherein said hyperglycemia.
12. one kind contains the insulin sensitizers and the Pharmaceutical composition of suitable carrier pharmaceutically, is used for the treatment of plasma glucose levels wherein and is being higher than the hyperglycemia of normal value to the≤126mg/dl scope.
CN98812083A 1997-10-13 1998-10-12 Use of thiazolidinediones for treatment of hyperglycaemia Pending CN1281359A (en)

Applications Claiming Priority (2)

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GB9721693.1 1997-10-13
GBGB9721693.1A GB9721693D0 (en) 1997-10-13 1997-10-13 Novel treatment

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JP (1) JP2001519382A (en)
KR (1) KR20010024481A (en)
CN (1) CN1281359A (en)
AP (1) AP2000001787A0 (en)
AU (1) AU9547098A (en)
BG (1) BG104404A (en)
BR (1) BR9815219A (en)
CA (1) CA2306086A1 (en)
CZ (1) CZ20001297A3 (en)
EA (1) EA002659B1 (en)
GB (1) GB9721693D0 (en)
HR (1) HRP20000255A2 (en)
HU (1) HUP0003922A3 (en)
ID (1) ID24521A (en)
IL (1) IL135513A0 (en)
NO (1) NO20001898L (en)
NZ (1) NZ503862A (en)
OA (1) OA11683A (en)
PL (1) PL339813A1 (en)
SK (1) SK5312000A3 (en)
TR (1) TR200000958T2 (en)
WO (1) WO1999018943A1 (en)
YU (1) YU28800A (en)

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Publication number Priority date Publication date Assignee Title
ATE186724T1 (en) * 1987-09-04 1999-12-15 Beecham Group Plc SUBSTITUTED THIAZOLIDINEDIONE DERIVATIVES
GB9218830D0 (en) * 1992-09-05 1992-10-21 Smithkline Beecham Plc Novel compounds
US5457109A (en) * 1993-09-15 1995-10-10 Warner-Lambert Company Use of thiazolidinedione derivatives and related antihyperglycemic agents in the treatment of disease states at risk for progressing to noninsulin-dependent diabetes mellitus

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BR9815219A (en) 2001-01-02
JP2001519382A (en) 2001-10-23
IL135513A0 (en) 2001-05-20
OA11683A (en) 2005-01-12
AU9547098A (en) 1999-05-03
HUP0003922A3 (en) 2001-12-28
AP2000001787A0 (en) 2000-06-30
GB9721693D0 (en) 1997-12-10
WO1999018943A1 (en) 1999-04-22
EA200000419A1 (en) 2000-10-30
CA2306086A1 (en) 1999-04-22
BG104404A (en) 2000-12-29
YU28800A (en) 2003-02-28
CZ20001297A3 (en) 2001-08-15
KR20010024481A (en) 2001-03-26
NZ503862A (en) 2003-01-31
EP1023056A1 (en) 2000-08-02
PL339813A1 (en) 2001-01-02
NO20001898L (en) 2000-06-09
TR200000958T2 (en) 2000-08-21
ID24521A (en) 2000-07-20
EA002659B1 (en) 2002-08-29
SK5312000A3 (en) 2000-09-12
NO20001898D0 (en) 2000-04-12
HUP0003922A2 (en) 2001-10-28
HRP20000255A2 (en) 2001-02-28

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