DE29924609U1 - Orally effective hypoglycemic compositions, useful e.g. for treating diabetes mellitus or hyperlipidemia, containing dipeptidyl peptidase IV effector and another antidiabetic agent - Google Patents

Abstract

New compositions (A) contain an effector (I) of dipeptidyl peptidase IV (or analogous enzyme activity) and another antidiabetic agent (II) (both optionally in salt form). An independent claim is included for pharmaceutical compositions comprising (I) and (II) (or their salts), together with pharmaceutical carriers and/or solvents. ACTIVITY : Antidiabetic; Antilipemic; Neuroprotective; Nephrotropic. MECHANISM OF ACTION : Dipeptidyl peptidase IV effector.

Description

The present invention relates to Dipeptide compounds or compounds analogous to dipeptide compounds, that from an amino acid and a thiazolidine or pyrrolidine group are formed, and their salts, hereinafter called dipeptide compounds, and their use the compounds for the treatment of impaired glucose tolerance, glucosuria, hyperlipidemia, metabolic acidosis, diabetes mellitus, diabetic neuropathy and nephropathy, as well as those caused by diabetes mellitus Consequences of mammals. The invention therefore also relates to a simple method for lowering the blood sugar concentration in mammals with the help of dipeptide compounds as activity-reducing Effectors (substrates, pseudo-substrates, inhibitors, binding proteins, antibodies u. a.) for Enzymes with comparable or identical activity to enzymatic activity of the enzyme dipeptidyl peptidase IV.

DP IV or DP IV analog activity (e.g. the cytosolic DP II has an almost identical one to the DP IV Substrate specificity) occurs in the bloodstream where it contains highly specific dipeptides from N-terminus of biologically active peptides split off when proline or Alanine represent the adjacent residues of the N-terminal amino acid in their sequence.

The glucose-dependent insulinotropic polypeptides: Gastric Inhibitory Polypeptides 1-2 (GIP _1-42 ) and Glucagon-Like Peptide Amide-1-736 (GLP- _1-7-36 ), _i.e. hormones that stimulate glucose-induced insulin secretion of the pancreas ( also called incretins), are substrates of the DP IV, since it can split off the dipeptides tyrosinyl-alanine or histidyl-alanine from the N-terminal sequences of these peptides in vitro and in vivo.

The reduction of such DP IV or DP IV analog enzyme activity to cleave such substrates in vivo can serve to reduce unwanted enzyme activity Laboratory conditions as well as with pathological conditions of Mammalian organisms suppress effectively. For example, is based on type II diabetes mellitus (also age diabetes) a reduced insulin secretion or disorders in the receptor function, among others in proteolytically caused concentration anomalies of Incretine justified are.

Hyperglycaemia and related causes or sequelae (including diabetes mellitus) are currently the technology by administering insulin (e.g. from bovine pancreas isolated or also genetically obtained material) to the sick Organisms treated in different forms. All so far known, as well as more modern processes, are characterized by high Material costs, high costs and often due to decisive impairments the quality of life of the patient. The classic method (daily IV insulin injection, common since the thirties Years) treats the acute symptoms of the disease, but leads after longer Application u. a. severe vascular changes (Arteriosclerosis) and nerve damage.

Recently the installation subcutaneous depot implants (insulin delivery is dosed, and the daily No injections) and implantation (transplantation) intact Langerhans cells in the dysfunctional pan kreas gland or other organs and tissues suggested. Such transplants are technically complex. Furthermore, they pose a risky surgical intervention in the recipient organism and require also for cell transplants according to methods of suppression or Bypassing the immune system.

The use of alanyl pyrrolidide and isoleucyl thiazolidide as inhibitors of DP IV or of DP IV analog enzyme activity is already from PCT / DE 97/00820 and the use of isoleucyl pyrrolidide and isoleucyl thiazolidide hydrochloride already known from DD 296 075. In this state of the art Isoleucyl-thiazolidide used is natural, thus L-threo-isoleucyl-thiazolidide: Zum priority date and on the filing date of the two publications, only this one was available, The natural Form of isoleucyl thiazolidide is available.

It has been found that this Compounds, especially L-threo-isoleucyl-thiazolidide, good effectors for DP IV and DP IV are analogous enzyme activities. When using this connection can some patients or forms of disease, however, have certain problems occur: depending on symptoms and severity e.g. diabetes mellitus, would it be e.g. desirable, Effectors available to have a different effect than the known compounds have: It is known that diabetes mellitus patients must be "adjusted" individually in order to to enable optimal treatment of their illness. So should some make e.g. decreased activity of DP IV effectors are sufficient. It could also be a high inhibitor activity and permanent administration of the same drug in particular undesirable side effects because of the lifelong duration of treatment have as a consequence. could continue it is also desirable be certain transport properties to increase the rate of absorption to improve the effectors in vivo.

The object of the invention is therefore new (especially activity-reducing) Effectors for the treatment of e.g. impaired glucose tolerance, glucosuria, hyperlipidemia, metabolic acidosis, diabetes mellitus, diabetic neuropathy and nephropathy, as well as those caused by diabetes mellitus Consequences of mammals and to provide a simple method of treating these diseases.

This object is achieved according to the invention the provision of dipeptide compounds or analogues of dipeptides, that from an amino acid and a thiazolidine or pyrrolidine group are formed, and their salts dissolved.

In the - preferably oral - administration of these effectors to a mammalian organism, the endogenous (or additionally exogenously administered) insulinotropic peptides GIP _1-42 and GLP- _1-7-6 (or GLP- _1-7-37 or their analogs) are obtained by DP IV or DP IV-like enzymes are degraded to a reduced extent and thus the concentration decrease of these peptide hormones or their analogues is reduced or delayed. The invention is therefore based on the finding that a reduction in the DP IV- or DP IV-like enzymatic activity acting in the bloodstream leads to an influence on the blood sugar level. It was found that

• 1. the reduction of DP IV or DP IV analog activity to relative increase in stability of the Glucose stimulated, or externally supplied incretins (or their Analogs), i.e. by applying effectors of the DP IV or DP IV anloger Proteins of incretin breakdown in blood can be controlled;
• 2. the increased biodegradability the incretins (or their analogues) have a change in activity endogenous insulin;
• 3. by reducing the DP IV or DP IV analog enzymatic activity increased stability of the blood Incretine in a subsequent change in glucose induced Insulin action results and thus one with DP IV effectors controllable modulation of blood glucose levels.

Dipeptide compounds according to the invention are in particular for this purpose suitable where the amino acid is from a natural one Amino acid, such as. Leucine, valine, glutamine, proline, isoleucine, asparagine or aspartic acid, selected becomes.

The oral application of the high affinity according to the invention, low molecular weight enzyme inhibitors is a less expensive Alternative e.g. on invasive surgical techniques in treatment pathological phenomena. Through chemical design of stability, transportation and clearance properties their mode of action can be modified and based on individual properties be coordinated.

As mentioned above, it e.g. be necessary in the long-term treatment of diabetes mellitus, To provide effectors with a defined activity with which in individual needs met by patients or symptoms can be treated. The dipeptide compounds according to the invention have therefore at a concentration (of the dipeptide compounds) of 10 μM, in particular under the conditions given in Table 1, a reduction in activity of dipeptidyl peptidase IV or DP IV-analogous enzyme activities of at least 10, preferably at least 40%. Is common also a decrease in activity of at least 60% or at least 70% is required. preferred Effectors can also a decrease in activity of maximum 20% or 30%. Furthermore, the transport properties of the present compounds, in particular by the peptide transporter Pep T1 significantly improved.

Particularly preferred dipeptide compounds are L-allo-isoleucyl-thiazolidide and its salts. These connections assign in proportion L-threo-isoleucyl-thiazolidide with approximately the same effect in terms of of glucose modulation surprisingly about five times better transport by the peptide transporter Pep T1.

Other preferred compounds will be given in Table 1.

The salts of the dipeptide compounds according to the invention can e.g. organic salts such as acetates, succinates, tartrates or fumarates or inorganic acid residues such as phosphates or sulfates. The are particularly preferred Fumarate, which has an excellent effect at a surprising high stability across from Have hydrolysis and are much less soluble than the hydrochloride. These properties are also advantageous in galenics.

Furthermore, L-threo isoleucyl pyrrolidide and its salts, especially the fumarate salts, and L-allo isoleucyl Pyrrolidide and its salts, especially the fumarate salts, are preferred.

The salts of the dipeptide compounds can be present in a molar ratio of dipeptide (analogue) component to salt component of 1: 1 or 2: 1. Such a salt is, for example, (Ile-Thia) ₂ fumaric acid.

Particularly preferred salts are Fumarate salts of L-threo-isoleucyl Thiazolidide and L-allo-isoleucyl thiazolidide.

The invention thus relates to effectors of dipeptidyl peptidase IV (DP IV) or DP IV-analogous enzyme activity and their use for lowering the blood sugar level below the glucose concentration in the serum of a mammalian organism which is characteristic of hyperglycemia. In particular, the invention relates to the use of the effectors of the DP IV or. DP IV-analogous enzyme activity to prevent or alleviate pathological metabolic abnormalities in mammalian organisms, such as impaired glucose tolerance, glucosuria, hyperlipidemia, metabolic acidosis, diabetes mellitus, diabetic neuropathy and nephropathy, and secondary diseases of mammals caused by diabetes mellitus. In a further preferred embodiment, the invention relates to a method for lowering the blood sugar level below the glucose concentration in the serum of an acid, which is characteristic of hyperglycemia ger organism, which is characterized in that a mammalian organism is administered a therapeutically effective amount of at least one effector according to the invention of DP IV or DP IV analog enzyme activity.

In a further preferred embodiment The invention relates to pharmaceutical compositions, that is to say medicaments, the at least one compound according to the invention or their salts optionally in combination with one or more pharmaceuticals acceptable carriers and / or contain solvents.

The pharmaceutical compositions can e.g. present as parenteral or enteral formulations and appropriate carrier contain or they can are available as oral formulations corresponding to the oral ones Administration of suitable carriers can contain. They are preferably in the form of oral formulations.

In addition, the pharmaceutical compositions one or more hypoglycaemic agents Contain active ingredients, which can be known active ingredients.

The effectors of the DP IV or the DP IV analog enzyme activity can to lower blood sugar levels among those for Hyperglycaemia characteristic glucose concentration in the serum of a mammalian organism or used to manufacture a corresponding drug become.

The effectors applied according to the invention DP IV or DP IV analog enzymes can be used pharmaceutically Formulations or formulation complexes as inhibitors, substrates, Pseudo substrates, inhibitors of DP IV expression, binding proteins or antibodies of these enzyme proteins or combinations of these various Substances that DP IV or. Reduce DP IV-analogous protein concentration in the mammalian organism, are used. Effectors according to the invention are e.g. DP IV inhibitors such as the dipeptide derivatives or dipeptide mimetics L-allo-isoleucyl-thiazolidide and the effectors given in Table 1 and their fumarate salts. The effectors according to the invention enable an individually adjustable treatment of patients or diseases, whereby in particular individually occurring intolerances, allergies and side effects can be avoided.

The connections also have different temporal courses effectiveness. This gives the treating doctor the opportunity handed over to the individual situation a patient's response on the one hand he can speed the onset of the effect and, on the other hand, the duration of the effect and especially the strength adjust the effect exactly ..

The method according to the invention represents a new kind Approach to lowering increased Blood glucose concentration in mammalian serum. It's easy to commercially usable and for use in therapy, in particular of diseases that are above average Blood glucose values are based in mammals and particularly in the Suitable for human medicine.

The effectors are e.g. in shape of pharmaceutical preparations administered the active ingredient in combination with usual Contain carrier materials known from the prior art. For example they become parenteral (e.g. IV, in physiological saline) or enterally (e.g. orally, formulated with usual support materials such as B. glucose) applied.

Depending on their endogenous stability and their bioavailability have to the effectors are given one or more times a day, to the desired one To achieve normalization of blood glucose levels. For example, can one such a dose range in humans in the range from 0.01 mg to 30.0 mg per day, preferably in the range of 0.01 to 10 mg effector substance per kilogram of body weight lie.

It has been found that by administering effectors of dipeptidyl peptidase I or DP IV-analogous enzyme activities in the blood of a mammal, through their associated temporary activity reduction, the endogenous (or additionally exogenously administered) insulinotropic peptides gastric inhibitory polypeptides 1 -42 (GIP _1-42 ) and glucagon-like peptides amide-1-736 (GLP- _1-7-6 ) (or GLP- _1-7-37 or their analogs) decreased by DP IV and DP IV-like enzymes are degraded and thus the decrease in concentration of these peptide hormones or their analogs is reduced or delayed. The increased stability of the (endogenously present or exogenously supplied) incretins or their analogues, which are achieved through the action of DP IV effectors, which are therefore increasingly available for the insulinotropic stimulation of the incretin receptors of the Langerhans cells in the pancreas, changes the effectiveness, among other things of the body's own insulin, which stimulates the carbohydrate metabolism of the treated organism.

As a result, the blood sugar level drops among those for hyperglycemia characteristic glucose concentration in the serum of the treated Organism. So that can Metabolic abnormalities such as impaired glucose tolerance, glucosuria, hyperlipidemia as well as possible severe metabolic acidosis and diabetes mellitus, clinical pictures the consequence of an over a longer period increased Blood glucose levels are prevented, alleviated.

In the series of the orally active antidiabetic agents known from the prior art, such an effective, low-molecular substance class (with the exception of the biguanide metformin: molecular weight 130) is not yet known. The molecular weights of the aminoacyl thiazolidides range from 146 (Gly cyl thiazolidide), 203 (isoleucyl thiazolidide) and 275 (tryptophanoyl thiazolidide). In comparison, the molecular weights of the sulphonylureas (glibenclamide: 494), the saccharides (acarbose: 630) and the thiazolidinediones (pioglitazone: 586) range from 500 to 700 Da. Physiologically, aminoacyl thiazolidides are hydrolyzed by aminopeptidases and by acid hydrolysis in the body's own substances, such as amino acids and cysteamine, so that the use of the compounds according to the invention as orally available antidiabetic agents is an enrichment of pharmacy.

In rats and mice it is experimentally induced hyperglycemia by oral administration with the compounds used according to the invention above average easy to treat (Tables 2 and 3). The administration of the 500 to 1000 times the effective dose resulted in no detectable pathological change while three weeks toxicological experiments on rats and mice.

The advantageous effect of compounds according to the invention on DP IV is exemplified in Table 1:

It is known that aminoacyl pyrrolidide and aminoacyl thiazolidide can be broken down by the enzymes proline aminopeptidase and prolidase present in the mucosal cells of the small intestine, in the serum and in liver cells and that the thiazolidine ring can be opened appropriately in the presence of acids (for example in the stomach) Cysteamine derivatives tends [cf. US 458407 ]. It was therefore surprising to find a dose-dependent effectiveness of the active substances after oral administration. The following table shows the dose dependency of the effect of L-allo-Ile-thiazolidide on serum DP IV activity after oral administration of L-allo-isoleucyl thiazolidide in healthy Wistar rats:

Extremely surprising and desirable is the glucose-reducing glucose achieved in the diabetic animal model Effect of the active ingredient according to the invention L-allo-isoleucyl thiazolidide after its oral administration simultaneous oral glucose stimulation (Table 3).

To strengthen the hypoglycemic Effects of different anti-diabetic drugs are often combinations of different orally effective anti-diabetic agents. Since the antihyperglycaemic effect of inventive effectors independently developed by other known orally administrable antidiabetic agents, the active compounds according to the invention are suitable analog in a corresponding galenical form to achieve the desired normoglycemic Effect, for use in combination therapies.

Thus, those used in the present invention can Compounds are converted into the customary formulations in a manner known per se, such as B. tablets, capsules, dragees, pills, suppositories, granules, Aerosols, syrups, liquid, solid and creamy emulsions and suspensions and solutions under Use of inert, non-toxic, pharmaceutically suitable carrier and Additives or solvents. Here are the therapeutically active compounds in each case preferably in a concentration of about 0.1 to 80, preferably from 1 to 50 percent by mass of the total mixture, i.e. in quantities, which are sufficient to increase the dosage range indicated to reach.

The good absorption of those used according to the invention Connections through mucous membranes of the gastrointestinal tract enables the use of many galenical preparations: the substances can be in the form of a drug of coated tablets, capsules, bite capsules, Tablets, drops, syrups, but also as suppositories or as nasal sprays be applied.

The formulations are, for example produced by stretching the active ingredient with solvents and / or carriers, optionally using emulsifiers and / or dispersants, where z. B. if water is used as a diluent, if necessary organic solvents as Cosolvents can be used.

Examples are auxiliary substances listed: Water, non-toxic organic solvents, such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. rapeseed oil, Peanut oil, sesame oil), alcohols (e.g. ethyl alcohol, glycerin), glycols (e.g. propylene glycol, polyetylene glycol); solid carriers, such as B. natural Rock flour (e.g. highly disperse silica, silicates), sugar (e.g. Raw, milk and dextrose); Emulsifiers, such as nonionic and anionic emulsifiers (e.g. olyoxyethylene fatty acid esters, Polyoxyethylene fatty alcohol ethers, Alkyl sulfonates and aryl sulfonates), dispersants (e.g. lignin, Lye, methyl cellulose, starch and polyvinyl pyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and Sodium lauryl sulfate) and optionally flavorings.

The application takes place in the usual Wise, preferably enterally or parenterally, especially orally. In the case of enteral use, tablets can be used in addition to mentioned carriers other additives such as sodium citrate, calcium carbonate and calcium phosphate with various additives, such as starch, preferably potato starch, gelatin and the like included. Lubricants, such as magnesium stearate, Sodium lauryl sulfate and talc can also be used for tableting. In the case of aqueous suspensions and / or elixirs for Oral applications are intended, the active ingredients can be used in addition to the above mentioned additives with various flavor enhancers or dyes are added.

With parenteral use can solutions of the active ingredients are used using suitable liquid carrier materials. In general, it has proven to be advantageous for intravenous administration Amounts of about 0.01 to 2.0 mg / kg, preferably about 0.01 to 1.0 mg / kg body weight per Day to achieve effective results, and at enteral application the dosage is about 0.01 to 2 mg / kg, preferably about 0.01 to 1 mg / kg body weight per day.

Nevertheless, it may be necessary be different from the amounts mentioned, depending on of body weight the test animal or patient or the type of application route, but also due to the animal species and their individual behavior across from the drug or interval at which the administration takes place. In some cases it can be sufficient with less than the aforementioned minimum amount get along while in other cases the specified upper limit was exceeded must become. In the case of application of larger quantities it may be advisable to give these in several single doses Day to distribute. For the application in human medicine is the same dosage range intended. Apply accordingly here also the above statements.

Examples of pharmaceutical formulations

1. Capsules with 100 mg L-allo-isoleucyl Thiazolidide per capsule:

A solution of the following composition is prepared for approx. 10,000 capsules: L-allo-isoleucyl thiazolidide hydrochloride 1.0 kg glycerin 0.5 kg polyethylene glycol 3.0 kg water 0.5 kg 5 kg

The solution is filled into soft gelatin capsules in a manner known per se. The capsules are suitable for biting or swallowing.

2. Tablets or coated tablets or coated tablets with 100 mg L-allo-isoleucyl thiazolidide: The following amounts relate to the production of 100,000 tablets: L-allo-isoleucyl thiazolidide hydrochloride, finely ground 10.0 kg glucose 4.35 kg lactose 4.35 kg Strength 4.50 kg Cellulose, finely ground 4.50 kg

The above ingredients are mixed and then made with a solution made from polyvinylpyrrolidone 2.0 kg polysorbate 0.1 kg and water approx.5.0 kg provided and granulated in a conventional manner by grating the moist mass and drying after adding 0.2 kg of magnesium stearate. The finished tablet mixture of 30.0 kg is processed into curved tablets weighing 300 mg. The tablets can be coated or coated in a manner known per se.

The technical data more preferred Connections are given below.

Measurement conditions for the K determination de substances

enzyme

DPIW _{sweat glands,} 0.75 mg / mL, 18 U / ml (GPpNA) in 25 mM Tris 7.6, 30% ammonium sulfate, 0.5 m M EDTA, 0.5 mM DTE stock solution: diluted 1: 250 in measuring buffer

buffer

40mM HEPES pH 7.6, I = 0.125 (KCl)

substratum

GPpNA * HCl stock solution: 2.1 mM

gauge

Perkin-Elmer Bio Assy Reader, HTS 7000 Plus, T = 30 ° C λ = 405nm

the mixture for measurement

100μl buffer 100μl substrate (3 different Concentrations 0.8mM - 0.2 mM) 50 ul Water / inhibitor (7 different concentrations 2.1μM - 32.8nM) 10μM enzyme

Buffer, water / inhibitor and enzyme were at 30 ° C preheated and the reaction by the addition of also preheated Substrate started.

Four determinations were carried out. The measuring time was 10 min.

Melting Point

Melting points were made on a case hot stage microscope Leica Aktiengesellschaft, the values are not corrected, or on a DSC device (at Heumann-Pharma).

Optical rotation

The rotation values were at different wavelength on a “polarimeter 341 "or higher from Perkin Elmer added.

Measurement conditions for mass spectrometry

The mass spectra were carried out on an “API 165” or “API 365” from PE Sciex recorded by electrospray ionization (ESI).

An approximate concentration of c = 10 μg / ml is used, the substance is taken up in MeOH / H ₂ O 50:50, 0.1% HCO ₂ H, and the infusion is carried out using a syringe pump (20 μl / min). The measurements were made in positive mode [M + H] *, the ESI voltage is U = 5600V.

Solubility study of the Salts of the Ile-Thia

• Ile-Thia * Fum weight 10.55 mg corresponds to 0.02 mmol (520.72 g / mol) addition of 100 μl H ₂ O _dest , 100 μl no solution, optical: no surface wetting from 200 μl successive start of solubility at 400 μl complete dissolution is observed 2.63% With this salt it was found that it is hardly wettable and does not decompose. Ile-Thia * Succ weight 16.6 mg corresponds to 0.031 mmol (522.73 g / mol) addition of 16 μl H ₂ O _dest , 16 μl no solution, optically “absorbing” the moisture of 66 μl – 1.5 ml none observe complete dissolution of the substance
• Ile-Thia * tartrate weight 17.3 mg corresponds to 0.049 mmol (352.41 g / mol) addition of 100 μl H ₂ O _dest , 100 μl complete dissolution 17.3%
• Ile-Thia * Phos weight 15.5 mg corresponds to 0.051 mmol (300.32 g / mol) addition of 100 μl H ₂ O, _dist. , 100 μl dissolving can be observed, successive addition of 100 μl H ₂ O at 400 μl complete dissolution 3.87%
• Ile-Thia * HCl weight 16.1 mg corresponds to 0.067 mmol (238.77 g / mol) addition of 100 μl H ₂ O, _dest , with 100 μl complete dissolution 16.1%

General synthesis Ile-Thia * salt

The Boc-protected amino acid Boc-Ile-OH is placed in ethyl acetate, the mixture is cooled to approx. -5 ° C. N-Metlylmorpholine is added dropwise, pivalic acid chloride (laboratory) or neoliexanoyl chloride (Technical center) is added dropwise under constant temperature. The reaction is stirred for a few minutes to activate. N-Metylmorpholine (laboratory) and thiazolidine hydrochloride (laboratory) are added dropwise in succession, thiazolidine (technical center) is added. The work-up in the laboratory is carried out traditionally with salt solutions, in the technical center the batch is cleaned with NaOH and CH ₃ OOOH solutions.

The Boc protective group is split off using HCl / dioxane (laboratory) or H ₂ SO (technical center).

The hydrochloride is made in the laboratory EtOH / ether crystallized.

In the technical center, the free amine is prepared by adding NaOH / NH ₃ . Fumaric acid is dissolved in hot ethanol, the free amine is added dropwise, (Ile-Thia) ₂ fumarate (M = 520.71 gmol ^-1 ) falls.

The analysis of isomers or enantiomers is done by electrophoresis.

Claims (11)

Composition comprising an effector of Dipeptidyl Peptidase IV or Dipeptidyl Peptidase IV analog enzyme activity and a another antidiabetic or its salts. A pharmaceutical composition comprising a Dipeptidyl peptidase IV or dipeptidyl peptidase IV analogue effector enzyme activity and another antidiabetic, or its salts, and one or several pharmaceutically acceptable carriers and / or solvents. The composition or pharmaceutical composition according to one of the preceding claims, characterized in that the effector consists of substrates, pseudo substrates, inhibitors, Binding proteins and antibodies selected becomes. The composition or pharmaceutical composition according to one of the preceding claims, characterized in that the effector is a dipeptide mimetic. The composition or pharmaceutical composition according to one of the preceding claims, characterized in that the effector is a dipeptide mimetic that contains an amino acid and comprises a pyrrolidine or thiazolidine group. The composition or pharmaceutical composition according to one of the claims 4 or 5, characterized in that the dipeptide mimetic L-threo-isoleucyl Pyrrolidine, L-threo-isoleucyl thiazolidine, L-allo-isoleucyl thiazolidine, L-allo-isoleucyl Pyrrolidine, glutaminyl pyrrolidine, glutaminyl thiazolidine, alanyl Thiazolidine, alanyl pyrrolidine, valyl thiazolidine and valyl pyrrolidine selected is. The composition or pharmaceutical composition according to one of the preceding claims, characterized in that the further antidiabetic from biguanides, sulphonylureas, saccharides and thiazolidinediones is. The composition or pharmaceutical composition according to claim 7, characterized in that the biguanide metformin is. The composition or pharmaceutical composition according to claim 7, characterized in that the sulphonyl urea Is glibenclamide. The composition or pharmaceutical composition according to claim 7, characterized in that the saccharide acarbose is. The composition or pharmaceutical composition according to claim 7, characterized in that the thiazolidinedione Is pioglitazone.