MXPA00011600A - New dipeptidyl peptidase iv effectors - Google Patents

Abstract

The invention relates to dipeptide compounds or compounds analogous to dipeptide compounds, which are made of an amino acid and a thiazolidine or pyrrolidine group, and to their salts. The invention further relates to the use of these compounds in the treatment of impaired glucose tolerance, glucosuria, hyperlipidemia, metabolic acidoses, diabetes mellitus, diabetic neuropathy and nephropathy as well as secondary diseases of diabetes mellitus in mammals.

Description

NEW EFFECTORS OF DIPEPTIDIL-PEPTIDASE IV The present invention relates to dipeptide compounds and compounds analogous to dipeptide compounds which are formed from an amino acid and a thiazolidine or pyrrolidine group, and salts thereof, hereinafter referred to as dipeptide compounds, and to the use of the compounds in the treatment of atrophied glucose tolerance, glycosuria, hyperlipidaemia, metabolic acidosis, diabetes mellitus, neuropathy and diabetic nephropathy and also of the sequelae of diabetes mellitus in mammals. Therefore, the invention also relates to a simple method to decrease the blood concentration of sugars in mammals with the help of dipeptide compounds as effectors of activity reduction (substrates, pseudo-treatments, inhibitors, binding proteins, antibodies, etc. .) for enzymes having the activity comparable to or identical to the enzymatic activity of the enzyme dipeptidyl-pept ida IV. The activity of DP IV or analogous to DP IV (for example, cytosolic DP II has a substrate specificity almost identical to DP IV) occurs in the bloodstream where the dipeptides are separated in a highly specific N-terminus of biologically active peptides when the proline or alanine are the adjacent residues of the N-terminal amino acid in their sequence. Glucose-dependent tropic insulinot polypeptides: inhibitory, gastric inhibitory polypeptide 1-2 (GIP? -2) and glucagon-like gone-amide-1 7-36 peptide (GLP-17-36), ie hormones that stimulate secretion induced by Insulin glucose by the pancreas (also called incretins), are substrates of the DP IV, since the latter is able to separate the t-irosinyl-alanine and histidyl-alanine dipeptides, respectively, from the N-terminal sequences of those peptides in vitro and in vivo. Reduction of this DP IV enzyme activity or analogous to DP IV of excision of those substrates in vivo can be used to produce effective suppression of undesired enzyme activity under laboratory conditions and also in the case of pathological conditions in mammalian organisms. For example, Type II diabetes mellitus (including adult onset diabetes) is based on reduced insulin secretion or disorders in receptor function that result inter alia from abnormal concentrations of incretin arising from proteolysis. According to the current state of the art, hyperglycemia and the causes and associated sequelae (including diabetes mellitus) are treated by the administration of insulin (for example, material isolated from bovine pancreas or obtained by genetic engineering techniques) to the diseased organism. in various forms of administration. All the methods known to date, including the most modern procedures, are distinguished by the requirement of a large quantity of material, by high costs and frequently by a deterioration different from the lived quality of the patients. The conventional method (i.v. insulin injection, daily, usual since the 1930s) treats the acute symptoms of the disease, but prolonged use leads inter alia to several vascular changes (arteriosclerosis) and nerve damage.

More recently, the installation of subcutaneous deposit implants has been proposed (insulin is released in dosed quantities, injections are unnecessary) and implantation (transplantation) of intact Langerhan cells in the functionally impaired pancreatic gland or in other organs and tissues. These transplants require a high level of technical resources. Additionally, they comprise a surgical intervention in the recipient organism, which is associated with risks and even in the case of cellular transplants, they require methods to suppress or evade the immune system. The use of alanyl pyrrolidide and isoleucyl thiazolidide as inhibitors of DP IV or analogous activity to DP IV is already known from PCT / DE 97/00820 and the use of sodium hydrochloride -pyrrole idide and isoleucyl- t iazolidide is already known from DD 296,075. The solvation of the iazolidide, which is used in the prior art, is natural, that is to say Lt reo-i soluci lt iazolidida: on the priority date and also on the date of application of the two specifications, only this form was available, the natural form, of the isoleucyl-thiazole idida.

It has been established that these compounds, especially the L-reo-isoleucyl-t-aiazolidide, are good effectors for the enzymatic activities of DP IV and analogous to DP IV, but the use of that compound may cause certain problems in the case of patients or some patients. forms of the disease. Depending on the symptoms and severity of for example diabetes mellitus, it would be desirable, for example, to make available effectors having an action different from that of the known compounds, for example, it is known that patients with diabetes mellitus should be "stabilized". "individually so that your disease can be treated in an optimal way. In some cases, for example, a reduction in activity by the DP IV effectors is sufficient. It is also possible that too high a level of inhibitory activity and permanent administration of the same drug, especially in view of the prolonged duration of treatment, may result in undesirable side effects. Additionally, it may also be desirable to improve certain transport properties in order to increase the absorption rate of the effectors in vivo. The purpose of the invention is therefore to provide new effectors (especially activity reducers) for the treatment of impaired tolerance to glucose, glycosuria, hyperlipidemia, metabolic acidosis, diabetes mellitus, neuropathy, diabetic nephropathy and also the sequelae of diabetes mellitus in mammals, and a simple method to treat these diseases. This purpose is achieved according to the invention by the provision of dipeptide compounds or dipeptide analogs which are formed from an amino acid and a thiazolidine or pyrrolidine group, and salts thereof. In the administration, preferably oral administration, of these effectors to a mammalian organism, endogenous endogenous (or additionally exogenously administered) peptides GIP? _42 and GLP-17_36 (or alternatively GLP-17_36 or analogs thereof) are they decompose to a reduced degree by the DP IV or DP IV type enzymes and therefore the decrease in the concentration of these peptide hormones or their analogs is reduced or delayed. Therefore, the invention is based on the finding that a reduction in the enzymatic activity of DP IV or type DP IV that acts in the blood circulation has an effect on the blood level of the sugar. It has been found that: 1. the reduction in the activity of DP IV or analogous to DP IV leads to an increase in the relative stability of the incretins introduced externally or stimulated by glucose (or analogues thereof), ie by the administration of DP IV protein effectors or DP IV analogs is possible to control the breakdown of incretin in the blood; 2. the increase in the biological decomposition stability of the incretins (or their analogues) results in a change in the action of the endogenous insulin; ! 3. The increment in the stability of the incretins caused by the reduction in the enzymatic activity of DP IV or analogous of DP IV in the blood results in a subsequent change in the insulin action induced by glucose and therefore in a modulation of the blood glucose level that is controllable by means of the DP IV effectors. Especially suitable for that purpose according to the invention are the dipeptide compounds in which the amino acid is selected from a natural amino acid, such as, for example, leucine, valine, glutamine, proline, isoleucine, asparagine and aspartic acid. The administration, where oral administration is possible, of the low molecular weight and high affinity enzyme inhibitors according to the invention is a cheaper alternative, for example, to invasive surgical techniques in the treatment of pathological symptoms. Through a chemical design of stability, transport and purification properties, its mode of action can be modified and correspond to the individual characteristics. As mentioned above, it may be necessary, for example in the case of the long-term treatment of diabetes mellitus, to provide effectors having a defined activity whereby it is possible to meet the individual needs of the patients and treat their symptoms. The dipeptide compounds according to the invention therefore exhibit at a concentration (of dipeptide compounds) of 10 μM, especially under the conditions indicated in Table 1, a reduction in the activity of the enzymatic activities of dipept-il-peptida IV. or analogous to DP IV of at least 10%, especially of at least 40%. Frequently, a reduction in activity of at least 60% or at least 70% is also required. Preferred effectors may also exhibit a reduction in activity of a maximum of 20% to 30%. Additionally, the transport properties of the present compounds, especially by the peptide carrier Pep TI, are significantly improved. Especially preferred dipeptide compounds are L-allo-iso-leucyl-t-aiazolidide and salts thereof. These compounds surprisingly exhibit an approximately fivefold improvement in transport by the Pep TI peptide transporter compared to L-threo-isoleucyl-thiazolidide, while having approximately the same degree of action with respect to glucose modulation. Additional preferred compounds are given in Taba 1. The salts of the dipeptide compounds according to the invention can be for example organic salts such as acetates, succinates, tartrates or fumarates or inorganic acid radicals such as phosphates or sulfates. Particular preference is given to fumarates, which have excellent action combined with a surprisingly high degree of stability towards hydrolysis and are considerably less soluble than hydrochlorides. These properties are also advantageous from the galenic point of view. Also preferred are L-t reo-isoleucyl-pyrrolidide and salts thereof, especially the fumaric salts and L-allo-isoleucyl-1-pyrrolidide and salts thereof, especially the fumaric salts. The salts of the dipeptide compounds can be present in a molar ratio of dipeptide component (-analog) to the salt component of 1: 1 or 2: 1. this salt for example is (Ile-Tia) 2 fumaric acid. Especially preferred salts are the fumaric salts of L-t-reo-isoleucyl-t-aiazolidide and L-al-l-1-thiazolidide soluci. Accordingly, the invention relates to effectors of the enzymatic activity of dipeptyl-peptidase IV (DP IV) or analogous to DP IV and its use in decreasing the blood level of sugar in the serum of a mammalian organism below the concentration of glucose that is characteristic of hyperglycemia. The invention relates especially to the use of the effectors of the DP IV or DP IV analog activity according to the invention in the prevention or alleviation of pathological metabolic abnormalities in mammalian organisms, such as, for example, glucose atrophied tolerance, glycosuria, hyperlipidemia, metabolic acidosis, diabetes mellitus, neuropathy and diabetic nephropathy and also the sequel of diabetes mellitus in mammals. In a further preferred embodiment, the invention relates to a compound for decreasing the blood level of sugar in the serum of a mammalian organism below the concentration of glucose that is characteristic of hyperglycemia, characterized in that it is administered to an organism mammal a therapeutically effective amount of at least one effector of DP IV or analogous DP IV enzyme activity according to the invention. In a further preferred embodiment, the invention relates to pharmaceutical compositions, ie medicaments comprising at least one compound according to the invention or a salt thereof, optionally in combination with one or more pharmaceutically acceptable carriers and / or solvents. The pharmaceutical compositions may be for example in the form of parenteral or enteral formulations and may contain appropriate carriers and may be in the form of oral formulations which may contain suitable carriers suitable for oral administration. Preferably, they are in the form of oral formulations. In addition, the pharmaceutical compositions may contain one or more active ingredients having a hypoglycemic action, which may be active ingredients known per se. The effectors of the DP IV or DP IV analog activity according to the invention can be used to lower the blood sugar level in the serum of a mammalian organism below the glucose concentration which is characteristic of hyperglycemia or for the production of a corresponding medicine. Effectors of the DP IV or DP IV analogous enzymes administered according to the invention can be used in pharmaceutically acceptable formulations or formulation complexes as inhibitors, substrates, pseudosust rats, inhibitors of DP IV expression, binding proteins or antibodies of these enzymatic proteins or combinations of these different substances that reduce the concentration of protein of DP IV or analogous to DP IV in the mammalian organism. The effectors according to the invention for example are inhibitors of DP IV such as the dipeptide derivatives or dipeptide mimics L-allo-isoleucyl-t-aiazolidide and the effectors indicated in Table 1 and fumaric salts thereof. The effectors according to the invention allow the treatment of patients and diseases to be adjusted individually, being possible in a special way to avoid intolerances, allergies and side effects that occur in individual cases. The compounds also exhibit different effective behaviors over time. As a result, the practitioner who carries out the treatment has the opportunity to respond in various ways according to the individual situation of a patient, is able, on the one hand, to adjust exactly the speed at which the action begins and on the other hand , the duration of action and especially the force of action. The method according to the invention represents a new class of method for decreasing the increased blood glucose concentrations in mammalian serum, is simple, capable of commercial exploitation, and suitable for use in therapy especially diseases that are based on values of blood glucose averaged above, in mammals and more especially in human medicine. The effectors are administered, for example, in the form of pharmaceutical preparations comprising the active ingredient in combination with customary carrier materials known in the prior art. For example, they were administered parenterally (eg, i.v., in physiological saline) or enterally (eg, orally, formulated with customary carrier materials, such as, for example, glucose). Depending on their endogenous stability and bioavailability, the effectors will need to be administered one or more times per day in order to achieve the desired normalization of blood glucose values. For example, this dose range in humans can be in the range from 0.01 mg to 30.0 mg per day, preferably in the range of 0.01 to 10 mg of effector substance per kilogram of body weight. It has been found that as a direct result of the administration of effectors of the enzymatic activities of dipept il-pept idase IV or analogous to DP IV in the blood of a mammal, by virtue of the associated temporal reduction in the activity thereof, endogenous rhoptic insulinot peptides (or additionally administered exogenously), polypeptide Gastric inhibitor 1-42 (GIP? _42) and peptide ido-amide-1 7-36 GLP-I7-36) glucagon type (or alternatively GLP-I7-37 or analogs thereof) are broken down to a reduced degree by DP enzymes IV or type DP IV and in this way the decrease in the concentration of these peptide hormones or their analogues is reduced or delayed. The increase in the stability of incretins (present endogenously or introduced exogenously) or their analogues caused by the action of the effectors of DP IV, with the result that the above are available in increased amounts for stimulation of insulinot ropic increment receptors of Langerhan cells in the pancreas, alters inter alia, the effectiveness of the body's own insulin, which results in a stimulation of metabolism of the carbohydrates of the treated organism. As a result, the blood sugar level in the serum of the organism being treated falls below the glucose concentration which is characteristic of hyperglycemia, thereby making it possible to prevent or alleviate metabolic abnormalities such as atrophied glucose tolerance, glycosuria, hyperlipidemia, and possible severe metabolic acidosis and diabetes mellitus, which are clinical syndromes resulting from elevated blood glucose levels over a prolonged period. Among the number of orally effective anti-diabetics known from the prior art, this class of effective low molecular weight substances has hitherto been unknown (with the exception of biguanide metformin: molecular weight 130). The molecular weights of the aminoacyl-thiazole dihydrates vary between 146 (glycidyl-thiazolidide) 203 (i soleulide-tolyzolide) and 275 (tryptophanyl thiazolidide). In comparison, the molecular weights of the sulfonylureas (glibenclamide: 494), saccharides (acarbose: 630) and zolidinadiones (piogli ta zol: 586) vary in the range of about 500 to 700 Da. In the body, the aminoacyl-t-aiazolidides are hydrolyzed by amino-peptidases and by acid hydrolysis to form endogenous substances, such as amino acids and cysteamine. Thus, the use of the compounds according to the invention as orally available antidiabetics constitutes pharmacological enrichment. In rats and mice, experimentally induced hyperglycemia can be treated to a better degree than average by oral administration of the compounds used according to the invention (Table 2 or 3). Administration of 500 to 1000 times the effective dose does not result in any demonstrable pathological change during the three-week toxicological experiments in rats and mice. The advantageous action of the compounds according to the invention in DP IV is shown by way of example in Table 1.

Table 1: Action of several effectors in the hydrolysis catalyzed by dipeptidyl-peptidase IV of 0.4 mM of the substrate H-Gly-Pro-pNA at 30 ° C, pH 7.6 and an ionic concentration of 0.125 Table 1 (continuation! It is known that amino acids 1-pi r rolides and aminoacyl-thiazolidides can be decomposed by the enzymes proline-aminopept idase and prolidase present in mucosal cells of the small intestine, in serum and in liver cells and that the thiazolidine ring has a tendency to open in the presence of acids (for example in the stomach) with the formation of the corresponding cysteamine derivative [see, US 458 407]. Therefore, it was surprising to find that the active ingredients have a dose-dependent effectiveness after per-oral administration. The dose dependence of the action of L-allo-Ile-iazolidide on the activity of DP IV in serum after oral administration of L-allo-iso-leucyl-thiazolidide to healthy Wistar rats is documented in the following Table: Table 2: Residual activity of DP IV in serum towards 0.4 mM of substrate H-Gly-Pro-pNA at 30 ° C, pH 7.6 and an ionic concentration of 0.125, after oral administration and depending on the dose of L-allo-isoleucyl-thiazolidide, determined 30 minutes after administration of the inhibitor Extremely surprisingly desirable is the glucose reducing action of the active ingredient L-allo-isoleucyl-thiazolidide according to the invention, achieved in the diabetic animal model after oral administration with an oral, synchronous glucose stimulation (Table 3) . In order to enhance the blood sugar reducing action of the various anti- diabetics, combinations of different orally effective anti- diabetics are frequently used. Since the anti-hyperglycemic action of the effectors according to the invention is exhibited independently of other known ant i -diabeteses administered orally, the active ingredients according to the invention are analogously suitable for use in therapies. of combination, in a suitable galenical form, to achieve the desired normoglycemic effect. Accordingly, the compounds used according to the invention can be prepared in a manner known per se in customary formulations, such as, for example, tablets, capsules, dragees, pills, suppositories, granules, aerosols, syrups, liquids, solid type emulsions. and cream and suspensions and solutions using inert carriers, additives or solvents, non-toxic, pharmaceutically acceptable. In these formulations, the therapeutically effective compounds in each case are preferably present in a concentration of about 0.1 to 80% by weight, preferably 1 to 50% by weight, of the total mixture, ie in sufficient amounts to achieve a dose within the indicated range.

Table 3: Reduction in circulating blood glucose within a period of 60 minutes after oral administration of 20 μM of L-allo-Ilethiazolidide to rats of several animal models with a synchronous glucose tolerance test (% data based on normoglycemic values) The good absorption of the compounds used according to the invention by the glucoses of the gastrointestinal tract allows a large number of galenic preparations to be used: The substances can be administered as medicaments in the form of dragees, capsules, capsules in pieces, tablets, drops and syrup, as well as the shape of pessaries and nasal sprays. The formulations are produced, for example, by spreading the active ingredient with solvents and / or carriers, optionally using emulsifiers and / or dispersing agents, and optionally, for example, where water is used as a diluent, organic solvents can be used as auxiliary solvents. . The following auxiliaries may be mentioned by way of example: water, non-toxic organic solvents such as paraffins (eg, mineral oil fractions), vegetable oils (eg, turnip oil, peanut, sesame) alcohols (eg, alcohol) ethyl, glycero), glycols (for example, propylene glycol, polyethylene glycol); solid carriers such as, for example, ground natural mineral oils (e.g., highly dispersed silicic acid, silicates), sugars (e.g., unrefined sugar, lactose and dextrose); emulsifiers, such as nonionic and anionic emulsifiers (for example, esters of polyoxyethylene fatty acids, ethers of polyoxyethylene fatty alcohols, alkylsulphonates and silicon phonates), dispersing agents (for example lignin, spent sulfite liquors) , methyl cellulose, starch and polyvinyl pyrrolidone) and glidants (for example, magnesium stearate, talc, stearic acid and sodium lauryl sulfate) and optionally flavoring agents. The administration is carried out in a conventional manner, preferably enterally or parenterally, especially orally. In the case of enteral administration, in addition to containing the mentioned carriers, the tablets may also comprise other additives such as sodium citrate, calcium carbonate, calcium phosphate, together with various complementary ingredients, such as starch, especially potato starch, gelatin and the like. It is also possible to use glidants, such as magnesium stearate, sodium lauryl sulfate and talc, for tabletting purposes. In the case of aqueous suspensions and / or opposing elixirs for oral uses, it is also possible that various flavor or coloring correctors are added to the active ingredients in addition to the auxiliaries mentioned above. For parenteral administration, it is possible to use solutions of the active ingredients using suitable liquid carrier materials. In the case of intravenous administration, it has generally been found to be advantageous to administer amounts of about 0.01 to 2.0 mg / kg, preferably about 0.01 to 1.0 mg / kg, of body weight per day in order to achieve effective results and in the case of enteral administration, the dose is from about 0.01 to 2 mg / kg, preferably about 0.01 to 1 mg / kg, of body weight per day. However, in some cases it may be necessary to deviate from the indicated amounts, depending on the body weight of the experimental animal or patient or the nature of the route of administration and also on the basis of the species of animal and its individual response to the medication or intervals. to which the administration is made. In some cases, for example, it may be sufficient to use less than the minimum amount mentioned above, while in other cases it will be necessary to exceed the aforementioned upper limit. Where relatively large amounts are administered it may not be advisable to divide the amount into several individual doses during the day. For use in human medicine, the same dose range is provided, the comments made above also apply accordingly.

Examples of pharmaceutical formulations 1. Capsules having 100 mg of L-allo-isoleucyl-thiazolidide per capsule: For approximately 10,000 capsules, a solution of the following composition is prepared: L-allo-isoleucyl-thiazolidide hydrochloride 1.0 kg Plicerol 0.5 kg Polyethylene glycol 3.0 kg water 0.5 kg 5.0 kg The solution is filled into soft gelatine capsules in a manner known per se. The capsules are suitable for chewing or swallowing. 2. Tablets / coated tablets or dragees that have 100 mg of L-allo-isoleucyl-thiazolidide: The following amounts are related to the production of 100,000: L-allo-isoleucyl-thiazolidide hydrochloride finely ground, 10.0 kg Glucose 4.35 kg Lactose 4.35 kg Starch 4.50 kg Cellulose, finely ground 4.50 kg The above constituents are mixed together and then combined with a solution, prepared from Polyvinylpyrrolidone 2.0 kg Polysorbate 0.1 kg and water approximately 5.0 kg and they are granulated in a manner known per se by scratching the wet mass and after the addition of 0.2 kg of magnesium stearate, it is dried. The finished 30.0 kg tablet mixture is processed to form dome-shaped tablets each weighing 300 mg. The tablets may be coated or coated with sugar in a manner known per se. The technical data of the preferred compounds are given below Tests in Ile-Tia * fumarate (isomer) and other salts IT * F = Isoleucyl-thiazolidide fumarate The NMR and HPLC data confirm the identity of the substances in question.

Measuring conditions for the determination of Ki of the substances Enzyme: DP IVriñón porcine 0.75 mg / ml, 18 U / ml (GPpNA) in Tris 25 mM pH 7.6, 30% ammonium sulfate, 0.5 mM EDTA, 0.5 mM DTE Concentrated solution: 1: 250 diluted in measuring buffer Shock absorber: 40 mM HEPES pH 7.6, 1 = 0.125 (KCl) Substrate: GPpNA * HCl Concentrated solution: 2.1 mM Measuring device: Perkin-Elmer Bio Test, HTS 7000 Plus, T = 30 ° C? = 405 nm Measurement Lot: 100 μl of buffer 100 μl of substrate (3 different concentrations 0.8 mM - 0.2 mM) 50 μl of water / inhibitor (7 different concentrations 2.1 μM - 32.8 nM) 10 μl of enzyme.

The buffer, water / inhibitor and enzymes were preheated to 30 ° C and the reaction was initiated by the addition of the substrate which was also preheated. The determinations were carried out four times. The measurement time was 10 minutes.

Determination of the melting point The melting points were determined in a Kofler heating platform microscope from Leica Akt iengesel lschaft, the values are uncorrected, or in a DSC apparatus (Heumann-Pharma).

Optical rotation The rotation values were recorded at different wavelengths in a "polarimeter 341" or higher, from the company Perkin-Elmer.

Measurement conditions for mass spectrometry The mass spectra were recorded by means of ionization of elect rorociado (ESI) in an "API 165" or "API 365" of the company PE Sciex. The operation is carried out using an approximate concentration of c = 10 μg / ml, the substance is taken in MeOH / H20 50:50, 0.1% HC02H, the infusion was carried out using a spray pump (20 μl / min) . The measurements are made in the positive mode [M + H] +, the ESI voltage is U = 5600V. The salts have the following data: Ile-Tia Ile-Tia salt solubility test * fu Amount weighed at 10.55 mg Corresponds to 0.02 mmol (520.72 g / mol) Addition of 100 μl H2Odestined • 100 μl no solution, visually: no surface wetting of 200 μl successive starting of solubility at 400 μl of complete solution was observed 2.63%. Therefore it is established that this salt is scarcely wettable and does not decompose.

Ile * Tia * succ Amount weighed at 16.6 mg Corresponds to 0.031 mmol (522.73 g / mol) Additional 16 μl H2Odismised • 16 μl no solution, visually: "sucked" from the moisture of 66 μl .1.5 ml no full dilution is observed of the substance Ile-Tia * tartrate Heavy amount in 17.3 mg Corresponds to 0.049 mmol (352.41 g / mol) Adi c ona l of 1 00 μl H2O dehydrated • 100 μl of complete dilution 17.3% Ile-Tia * phos Heavy amount in 15.5 mg Corresponds to 0.051 mmol (300.32 g / mol) Adi ci ona l of 100 μl H2Odestiiada • 100 μl is observed of slight dilution successive addition of 100 μl of H20 to 400 μl full dilution 3.87% Ile-Tia * HCl Amount weighed at 16.1 mg Corresponds to 0.067 mmol (238.77g / mol) Additional 100 μl H2O-depleted • To 100 μl of complete dilution 16.1% General synthesis of Ile-Tia * salt The amino acid protected by Boc-Ile-OH is placed in ethyl acetate and the batch is cooled to approximately -5 ° C. N-met i lmorfolin, pivalic acid chloride (on a laboratory scale) or neoxanoyl chloride (on a pilot plant scale) is added dropwise at a constant temperature. The reaction is stirred for a few minutes for activation. N-methylmorpholine (laboratory scale) and thiazolidine hydrochloride (laboratory scale) are added dropwise in succession, thiazolidine (pilot plant scale) is added. The elaboration of laboratory work is carried out in a conventional manner using saline solutions on a pilot plant scale, the batch is purified with NaOH and CH3COOH solutions. The removal of the Boc protecting group is carried out using HCl / dioxane (laboratory scale) or H2S04 (pilot plant scale). In the laboratory, the hydrochloride is crystallized from EtOH / ether. On a pilot plant scale the free amine is prepared by the addition of NaOH / NH3. the fumaric acid was dissolved in hot methanol, the free amine is added dropwise, and the fumarate of (Ile-Tia) 2 is precipitated (M = 520.71 gmol "1) - The isomer and enantiomer analyzes are carried out by electrophoresis .

Methods and measurement conditions CE investigations carried out using an "MDQ P / ACE® system" from the company Beckmann Operating conditions Shock absorber: 20 mM phosphate pH 7.0, b-hydroxypropyl-cyclodextrin 100 mM Capilarity 50/60. 2 cm, internal diameter 25 mm, coated with acrylamide Voltage: 10 kV Detection: photodiode array detector at 214 nm Temperature: 7 ° C

Claims (22)

1. CLAIMS 1. Dipeptide mimetics formed from an amino acid and a thiazolidine or pyrrolidine group, specifically L-allo-isoleucyl-thiazolidine, L-allo-isoleucyl-pyrrolidine, and salts of the same.
2. 2. Dipeptide mimetics according to claim 1, characterized in that the salts are organic salts such as acetates, succinates, tartrates or fumarates, or radicals of inorganic acids such as phosphates or sulfates.
3. 3. Salts of dipeptide mimics according to any of the preceding claims, characterized in that they are present in a molar ratio of dipeptide component to salt component of 1: 1 or 2: 1.
4. 4. Salts of dipeptide mimics according to any of the preceding claims, specifically fumaric salts.
5. 5. Salts of dipeptide mimics according to claim 4, specifically fumaric salts of L-allo-isoleucyl-thiazolidine.
6. 6. Salts of dipeptide mimics formed from an amino acid and a thiazolidine or pyrrolidine group, specifically salts of L-t reo-isoleucyl-thiazolidine and L-t reo-isoleucyl-pyrrolidine.
7. 7. Salts according to claim 3, specifically organic salts.
8. 8. Salts according to claim 6, specifically succinates, tartrates fumarates and hydrochlorides.
9. 9. Pharmaceutical composition, characterized in that it comprises at least one compound according to any of the preceding claims, optionally in combination with one or more pharmaceutically acceptable carriers and / or solvents.
10. 10. The pharmaceutical composition according to claim 9, characterized in that the carrier is a carrier for parenteral or enteral formulations.
11. 11. The pharmaceutical composition according to claim 9, characterized in that it is present in a formulation for oral administration.
12. 12. The pharmaceutical composition according to any of claims 9 to 11, characterized in that it additionally comprises an active ingredient having hypoglycemic action.
13. 13. The use of at least one compound or pharmaceutical composition according to any of the preceding claims in the production of a medicament for reducing the activity of enzymatic activities of dipept il-peptida IV or analogous to dipeptyl-peptidase IV. The use of at least one compound or composition according to any of claims 1 to 12 in the production of a medicament for lowering the blood sugar level below the glucose concentration which is characteristic of hyperglycemia in the serum of a mammal. 15. The use of at least one compound or composition according to any of claims 1 to 12 in the production of a medicament for the oral treatment of metabolic disorders associated with diabetes mellitus. 16. The use of at least one compound or composition according to any of claims 1 to 12 in the production of a medicament for the treatment of atrophied glucose tolerance, glycosuria, hyperlipidemia, metabolic acidosis, diabetes mellitus, neuropathy and diabetic nephropathy and also of sequels of diabetes mellitus in mammals. 17. The use of at least one dipeptide mimic formed from an amino acid and a thiazolidine or pyrrolidine group, and salts thereof, wherein the amino acid is selected from leucine, glutamine, proline, asparagine and aspartic acid in the production of a drug to lower the blood sugar level below the glucose concentration that is characteristic of hyperglycemia in the serum of a mammal. The use according to claim 17, characterized in that the salts are organic salts such as acetates, succinates, tartrates or fumarates, or radicals of inorganic acids such as phosphates or sulfates. The use according to claim 17 or 18, characterized in that the salts are present in a molar ratio of dipeptide component to salt component of 1: 1 to 2: 1. 20. The use according to any of claims 17 to 19, where the salts are fumaric salts. 21. The use according to any of claims 17 to 20, in the production of a medicament for the oral treatment of metabolic disorders associated with diabetes mellitus. 22. Use according to any of claims 17 to 21, in the production of a medicament for the treatment of atrophied glucose tolerance, glycosuria, hyperlipidemia, metabolic acidosis, diabetes mellitus, neuropathy and diabetic nephropathy and also of the sequelae of diabetes mellitus in mammals. - * - - -