Treatment of diabetes with thiazolidinedione, insulin secretagogue and diguanide

Treatment of diabetes with thiazolidinedione

Stimulates the secretion of insulin and diguanide

Full description

Background of the invention

This invention relates to a method of treating, namely a method of treating diabetes mellitus, in particular non-insulin-dependent diabetes mellitus (NIDDM) (or type 2 diabetes) and conditions associated with diabetes.

Insulin-promoting substances are compounds that promote increased secretion of insulin by pancreatic beta cells.

Sulphonylureas are well-known examples of substances that stimulate insulin secretion. Sulphonylureas act as anti-hyperglycemic agents and are used in the treatment of diabetes (type 2). Examples of sulphonylureas include glibenclamide, glipizide, gliclazide, glimepiride, tolazamide, and tolbutamide.

Biguanide antihyperglycemic agents are commonly used in the treatment of diabetes (type 2). 1,1-Dimethylbiguanidine (or Metformin) is an example of a biguanide antihyperglycemic agent.

European Patent Application Publication No. 0306228 relates to certain thiazolidinedione derivatives disclosed to have antihyperglycemic and antihyperlipidemic activity. One of the vehicles

The special thiazolidinedione disclosed in European Patent No. 0306228 is

5 - [4-[2-N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4- dione (later in this patent &compound (I)). International Application 05659/94 discloses certain salts of compound (I), including the maleate salt.

Compound I is an example of a class of anti-hyperglycemic agents known as “insulin sensitisers.” Compound I, in particular, is a thiazolidinedione.

Thiazolidinedione is an insulin sensor.

European patent applications reveal: 0008203, 139421, 0032128, 0428312, 0489663, 0155845, 0257781, 0208420, and 0177353

, 0319189, 0332331, 0332332, 0528734, and 0508740

International Patent Application, Bulletins Nos. 92/18501, 02079/93, and H93/2244

And US patent numbers 5,104,888 and 5,478,852, also for sensors

Certain insulin sensitizers, lithazolidinedione diuretics.

Another series of compounds generally known to have insulin sensing activity are those represented by the compounds disclosed in international patent applications, patents

Nos. 93/21166 and 94/01420. In this patent, these compounds are referred to as “cyclic insulin sensitisers”. Other examples of cyclic insulin sensitisers are those disclosed in US Patent No. 5,232,945 and International Applications, Publications Nos. 92/03425 and 19702/91.

Examples of insulin sensitizers include those disclosed in the European patent application, Publication No. 0533933, the Japanese patent application, Publication No. 0527120, and the US patent No. 526445.

General description of the invention

It is now surprisingly shown that compound I in combination with an insulin secretagogue and the antihyperglycemic agent biguanide provides a particularly beneficial effect on blood sugar control, and such a combination is therefore particularly useful for the treatment of diabetes mellitus, in particular Especially type 2 diabetes and diabetes-related conditions. It is also indicated that treatment should continue with minimal side effects.

A pharmaceutical composition for the treatment of diabetes and diabetes-related conditions in a mammal with a beneficial effect on blood sugar control, comprising: 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy] Benzyl]thiazolidine-2,4- dione (compound I) or its pharmaceutically acceptable form in an amount of 2 to 12 mg, an insulin secretagogue and an anti-hyperglycemic agent, guanide. biguanide

The pharmaceutical formulation of the invention is useful in a method for treating diabetes, in particular type 2 diabetes, and conditions associated with diabetes, in a mammalian organism, such as a human being, wherein the method comprises administering an effective, non-toxic, pharmaceutically acceptable amount of an insulin sensitiser and an excitant. To secrete insulin and the anti-hyperglycemic agent biguanide, to a mammalian organism that needs it.

The method comprises either co-administration or contractual administration of an insulin sensitiser, an insulin secretagogue, and the anti-hyperglycemic agent biguanide.

Coadministration includes the administration of a formulation comprising an insulin sensor, an insulin secretagogue and a biguanide antihyperglycemic agent or essentially simultaneous administration of separate formulations of each agent.

In another aspect, the invention provides for the use of an insulin sensor, such as compound (I), an insulin-secreting substance and an anti-hyperglycemic agent biguanide, in the manufacture of a composition for the treatment of diabetes, particularly type 2 diabetes and conditions associated with diabetes.

A suitable insulin sensitiser is a thiazolidinedione insulin sensitiser. A suitable insulin sensitiser is a compound (I).

Insulin sensitizers include thiazolidinedione

Other occasion on:

-2-5-[[4-[(3,4- dihydro-6-hydroxy-2, 5, 7,8-tetramethyl-2H- 1 -benzopyran-(+)

yl)methoxy]phenyl]methyl]-2,4-thiazolidinedione

(or troglitazone) or

5-[4-[(1- methylcyclohexyl)methoxy]benzyl]thiazolidine-2,4-dione or ciglitazone), or 5-[4-[2-(ethylpyridin-2-yl)ethoxy]benzyl) thiazolidine-2 ,4-dione or (pioglitazone) or

5-[(benzyl-2,3-dihydrobenzopyran)-5-ylmethyl)thiazolidine-2,4-dione or (englitazone).

Suitable substances that stimulate insulin secretion include sulphonylureas.

A suitable biguanide antihyperglycemic agent is metformin, buformin, or phenformin, especially metformin. metformin

The method includes giving 2 to 1.2 mg of compound (I), especially when given as a whole

today.

In particular, the method involves administering 2 to 4, 4 to 8, or 8 to 2 1 mg of compound I each day.

In particular, the method involves administering 2 to 4 mg of compound I, especially when given every day.

In particular, the method involves administering 4 to 8 mg of compound I, especially when given every day.

In particular, the method involves administering 8 to 12 mg of compound I, particularly when given every day.

Preferably, the method involves administering 2 mg of compound I, particularly when given every day.

Preferably, the method involves administering 4 mg of compound I, particularly when given every day.

Preferably, the method involves administering 8 mg of compound I, particularly when given every day.

It will be understood that both the insulin sensitiser, such as compound (I), and the antihyperglycemic agent biguanide are administered in a pharmaceutically acceptable form, including pharmaceutically acceptable derivatives such as their salts, esters, and pharmaceutically acceptable solutes, as appropriate. In certain cases in this patent the names used may relate to substances stimulating insulin secretion

closely related insulin and antihyperglycemic agents biguanide in a special pharmaceutical form of the appropriate active agent; It will be understood that all pharmaceutically acceptable forms of active agents are inherently patent.

We designate the appropriate pharmaceutically acceptable salt forms of insulin sensors, such as Compound (I), to those forms described in the patents and patent applications referred to, for example, in European Patent Application No. 0306228 and International Application No. 94/056 for Compound (I). The preferred pharmaceutically acceptable salt of compound (I) is maleate.

Suitable pharmaceutically acceptable salt forms for insulin sensors, such as compound (I), include those described in patents and patent applications referred to before, for example in European Patent Application No. 0306228 and International Application No. 94/056 for compound (I), and in particular the hydrate compounds hydrates.

Suitable pharmaceutically acceptable forms of the insulin secretagogue and the antihyperglycemic agent biguanide depend on the particular compound used but are based on known pharmaceutically acceptable forms of the particular compound.

Suitable sulphonylureas include glibenclamide, glipizide, gliclazide, glimepiride, tolazamide, and tolbutamide.

Additional sulphonylureas include acetohexamide

Carbutamide, chlorpropamide, and glibornuride

And gliquidone, glisentide, glisolamide, and glysoxibide.

glisoxepide, glyclopyamide, and glycylamide.

Additional suitable insulin secretagogues include repaglinide. selected repaglinide These derivatives are found or cited in standard reference texts such as the British and American Pharmacopoeia (Marck Publishing Co.'s Remington's pharmaceutical).

sciences, and Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press)

(See, for example, Issue 31, page 341, and the pages mentioned in this patent.)

Insulin sensors, such as compound I, their pharmaceutically acceptable salt, or their pharmaceutically acceptable solutes, may be prepared using known methods, for example those disclosed in the patents and patent applications referred to before, such as European Patent Application No. 0306228 and the International Application 94/05659 for compound (I). The aforementioned patent lists and patent applications, such as European Patent Application No. 0306228 and International Application No. 94/05659, are incorporated into this patent by reference.

A compound (I) may exist in one of the tautonteric forms, each of which is included by the compound expression (I) as individual tautomeric forms, or as mixtures thereof. Compound (I) contains a chiral carbon atom, and thus it can exist in up to two stereoisomeric forms. The compound expression (I) includes all isomeric forms, whether individual isomers or mixtures of isomers, including Racemates.

The substance that stimulates insulin secretion and the anti-diabetic agent biguanide of choice are prepared according to well-known methods, and many of these methods exist. Or they are referenced in standard reference texts such as the British and American Pharmacopoeia:

Marck Publishing Co. (Remington's pharmaceutical sciences), and Martindale The Extra

Pharmacopoeia (London, The Pharmaceutical Press

(See, for example, Issue 31, page 341, and the pages mentioned in this patent.)

The term 'conditions associated with diabetes' when used herein refers to conditions associated with diabetes melius itself and complications associated with diabetes. Also included in the expression &conditions associated with diabetes are those conditions associated with the pre-diabetic state. The term &conditions associated with the pre-diabetic state& includes conditions such as insulin resistance; Including hereditary insulin resistance, poor glucose tolerance and hyperinsulinemia.

The term “conditions associated with diabetes itself” includes hyperglycaemia and insulin resistance, including acquired insulin resistance. Additional conditions associated with diabetes mellitus itself are on the rise

Blood pressure, cardiovascular disease, especially atherosclerosis, and conditions associated with insulin resistance. Conditions associated with insulin resistance include polycystic ovarian syndrome, steroid-induced insulin resistance, and gestational diabetes. 'Complications associated with diabetes mellitus' includes renal disease, especially renal disease associated with Type 2 diabetes, neuropathy and retinopathy.

The expression “complications associated with diabetes” includes diabetes mellitus, particularly renal disease associated with Type 2 diabetes, neuropathy, and retinopathy. Renal diseases associated with type 2 diabetes include nephropathy, glomerulonephritis, glomerular sclerosis, hypertensive nephrosclerosis, and end-stage kidney disease. Kidney diseases associated with type 2 diabetes include nephrotic syndrome.

For the avoidance of doubt, when reference is made in this patent to non-vector quantities, including mg quantities of compound (I) in a pharmaceutically acceptable form, the indicated non-vector quantities shall be prepared with respect to compound (I) itself: for example, 2 mg of compound (I) in salt form

Maleate salt is the amount of maleate salt that contains 2 mg of compound (I).

Diabetes is preferably type 2 diabetes.

The particularly beneficial effect on blood sugar control provided by the remedy of the invention is to be synergistic with respect to the expected control of the sum of the effects of the individual active agents. Appropriately, the insulin sensitiser is the first administering agent. Blood sugar control may be characterized using conventional methods, for example by measuring an indicator typically used for blood sugar control such as fasting plasma glucose or glycosylatedhaemoglobin (HbAle). Such indicators are determined

Using standard methods, for example those described in:

Tuescher A, Richterich, p., Schweiz, med. Wschr. 101 (1971), 345 and 390 and Frank P., 'Monitoring the Diabetic Patent with Glycosolated Hemoglobin Measurements', Clinical Products 1988

In a favorable aspect, the dose level of each of the active agents when used in accordance with the treatment of the invention will be less than would be needed for a pure additive effect on blood sugar control.

There is also evidence that the treatment of the invention will produce an improvement, with respect to individual agents, in the levels of advanced glycosylation end products (AGES) and leptin.

Serum lipids, including total cholesterol and cholesterol. HDL cholesterol and LDL cholesterol, including improvements in their ratios, specifically improvements in serum lipids, including total cholesterol, HDL cholesterol, and LDL cholesterol, including an improvement in their ratios.

As used herein, the expression 'pharmaceutically acceptable' includes both human and veterinary use: for example the expression 'pharmaceutically acceptable' includes a compound that is veterinary acceptable.

In the method, the active drugs are preferably administered in the form of a pharmaceutical formulation. As previously indicated, such combinations may include all of the drugs or only one of the drugs.

Accordingly, in one aspect the present invention provides a pharmaceutical composition comprising an insulin sensor, such as compound (I) and in particular 2 to 1 mg thereof, an insulin-secreting substance, an anti-hyperglycemic agent biguanide, and a pharmaceutically acceptable carrier for this purpose. .

Such compositions may be prepared by mixing an insulin sensor, such as compound I, in particular 1 to 2 mg thereof, an insulin secretagogue, an antihyperglycemic agent biguanide, and a pharmaceutically acceptable carrier for the purpose.

The formulations are usually adapted for oral administration. However, it may be adapted for other routes of administration, for example non-enteral administration, sublingual administration or transdermal administration.

Compositions may be in the form of tablets, capsules, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations, such as sterile oral solutions or suspensions. For non-enteral use. In order to obtain consistency of administration, it is preferable that the composition of the invention be in the form of a unit dose.

Unit dosage forms may be tablets and capsules and may contain conventional excipients such as binding agents - eg SUP syrup, acacia gum, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol, or glycine; And tablet formulation lubricants lubricants, eg magnesium stearate; and disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate, or microcrystalline cellulose; Or pharmaceutically acceptable wetting agents such as sodium lauryl sulfate. sulphate

The compositions are preferably in unit dosage form in an amount appropriate for the appropriate daily dose. Suitable doses of insulin sensitisers include those disclosed in the patents and patent applications referenced above.

Suitable doses, including dosage units, of compound (I) include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11. Or 12 mg of compound (I).

In treatment, medications may be given 1 to 6 times each day, but most preferably 1 or 2 times daily.

The specific doses of compound (I) are 2 mg/day and 4 mg/day, including 2

mg twice daily, and 8 mg/day, including 4 mg twice daily. Appropriate doses, including dose units for an insulin secretagogue, such as a sulphonylurea, or the antidiabetic agent biguanide, include known doses, including dose units, for these compounds as described or referenced in standard reference texts such as constitutions British and American medicines

Marck Publishing Co. (Remington's pharmaceutical sciences), and Martindale The Extra (Pharmacopoeia (London, The Pharmaceutical Press) (see, for example, 31st Edition, page 341, and pages cited herein). Thus, for sulphonylureas, a typical daily dose is of glibenclamide in the range of 2.5 to 20 mg, for example 10 mg twice daily or 20 mg.

mg once daily; A typical daily dose of glipizide is in the range of 2.5 to

40 mg; A typical daily dose of gliclazide is in the range of 40 to 320 mg; A typical daily dose of tolazamide is in the range of 100 to 1000 mg; A typical daily dose of tolbutamide is in the range of 1,000 to

3000 mg; A typical daily dose of chlorpropamide is in the range of 100 to 500 mg; A typical daily dose of gliquidone is in the range of 15 to 180 mg.

Repaglinide may be taken in amounts, usually in the range of 0.5 mg to 4 mg and usually with meals, up to a typical maximum daily dose of 16 mg per day. For biguanide antidiabetic agents, appropriate doses of metformin include up to 3,000 mg every day, and in dosage units of 500 mg (e.g., two or three times daily) or 850 mg (e.g., twice daily), one of Example dosage for metformin is 500 mg one to five times each day.

Solid oral compositions may be prepared by conventional methods of mixing, filling, or tableting. Repeated mixing operations may be used to distribute the active agent throughout these formulations using large amounts of fillers. Such operations are of course conventional in the field. Diseases may be packaged according to methods well known in standard pharmaceutical practice, in particular by enteric coating.

Oral liquid preparations may be, for example, in the form of emulsions, syrups, or elixirs, or they may be presented as a dry product for reconstitution with water or another suitable carrier before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, or aluminum stearate gel. aluminum stearate gel, or hydrogenated edible fats; and emulsifying agents, eg lecithin, sorbitan monooleate, or gum acacia, and non-aqueous vehicles (which may include edible oils), for example almond oil or ftactionated coconut oil, or oily esters such as esters of glycerine, or propyl esters propylene glycol, or ethyl alcohol; Or preservatives, for example methyl, propyl p-hydroxybenzoate, or sorbic acid, and, if desired, conventional flavoring agents or agents. Coloring. For non-enteral administration, fluid dosage unit forms are prepared using the compound and a sterile carrier and, depending on the concentration used, can be either suspended or dissolved in a carrier. In preparing solutions, the compound can be dissolved in water for injection and sterilized by filtration before filling in a suitable vial or ampoule and sealing it tightly. Advantageously, auxiliaries such as local anesthetics, preservatives and pH regulators can be dissolved in the carrier. To enhance stability, the formulation may be frozen after filling in the vial and removing water under vacuum. Suspensions are prepared for different methods

Enteric in much the same manner, except that compound I is suspended in the carrier rather than dissolved, and sterilization cannot be accomplished by filtration. The compound may be sterilized by exposure to ethylene oxide before suspension in the carrier. Advantageously, a surfactant or wetting agent is included in the formulation to facilitate uniform distribution of the compound.

The compositions may contain from 99 to 99% by weight, and preferably 10 to 60% by weight, of the active ingredient depending on the method of administration.

The composition may, if desired, be in the form of a package accompanied by written or printed instructions for use.

The compositions are prepared and formulated according to traditional methods, such as those disclosed in standard reference texts such as the British and American Pharmacopoeia.

Marck Publishing Co.) Remington's pharmaceutical sciences), and Martindale The Extra (Pharmacopoeia (London, The Pharmaceutical Press) (see, for example, 31st Edition, page 341, and pages cited herein). The present invention also provides a pharmaceutical composition comprising an insulin sensor, Such as compound (I), especially 2 to 12 mg of it, a substance that stimulates insulin secretion, an anti-hyperglycemic agent biguanide, and a pharmaceutically acceptable carrier substance for this purpose, for use as an effective therapeutic substance.

The present invention also provides for the use of compound (I) in an amount of 2 to 12 mg, an insulin secretagogue and an anti-hyperglycemic agent biguanide to manufacture a drug for the treatment of diabetes and diabetes-related conditions in a mammal. The range of 2 to 4 mg includes a range of 2.1 to 4; or 2.2 to 4; or 2.3 to 4; or

2.4 to 4; or 2.5 to 4; or 2.6 to 4; or 2.7 to 4; or 2.8 to 4; or 2.9 to 4; or

3 to 4 mg.

The range of 4 to 8 mg includes a range of 4.1 to 8; or 4.2 to 8; or 4.3 to 8; or.

4.4 to 8; or 4.5 to 8; or 4.6 to 8; or 4.7 to 8; or 4.8 to 8; or 4.9 to 8;

or

5 to 8; or 6 to 8; Or 7 to 8 mg.

The range of 8 to 2 1 mg includes a range of 8.1 to 12; or 8.2 to 12; or 8.3 to 12; or 8.4 to 12; or 8.5 to 12; or 8.6 to 12; or 8.7 to 12; or 8.8 to 12; Or 8.9

to 12; or 9 to 12; And 10 to 12, or 11 to 12 mg.

No toxic adverse effects of the compositions or methods of the invention are expected within the range values indicated above.

Composition of the compound (1)

Preparation of concentrate: A tablet forming concentrate was prepared using the following materials

<img file="SA1657B1_D0001.tif" />

*Removed during processing. The concentrate was then formulated into tablets using the following:

<img file="SA1657B1_D0002.tif" />

The compositions of the other active agents are as described in the above-referenced publications.