Application of sibutramin analogs for preventing diabetes mellitus

FIELD: medicine, endocrinology.

SUBSTANCE: the present innovation deals with preventing diabetes mellitus and its aftereffects. It is suggested to apply sibutramin and its analogs to decrease non-susceptibility to insulin in diabetes-free patients, prevent decreased tolerance to glucose and decrease the quantity of introduced insulin in diabetes-suffering patients and normalize body weight, as well.

EFFECT: higher efficiency of application.

28 cl, 3 dwg, 1 tbl

 

The invention relates to a method of reducing resistance to insulin in people who have not had reduced glucose tolerance (IGT) and insulin-independent diabetes mellitus (NIDDM).

Currently, the individual, the content of glucose in the plasma of fasting which more than 7.8 mmol/l, defined as suffering from diabetes mellitus (although this is currently under revision and will soon be installed at a lower level, between 6 and 7 mmol/l). However, there is a standard method of determining suffer if the individual has diabetes or not, and it is important, if an individual on an empty stomach is the concentration of glucose in plasma is somewhat lower than the above content. This method is called oral test glucose tolerance (PTH).

Pttg carried out as follows. After an overnight fast for 10-16 hours register contents blood glucose on an empty stomach. Glucose (75 g) administered orally in water (250-300 ml). Following the registration of glucose in the blood is carried out in 2 hours. Diabetes is diagnosed if the fasting glucose is more than 7.8 mmol/l, or if the content of 2 hours is more than 11.1 mmol/L. Reduced glucose tolerance (IGT) diagnosticul if the fasting glucose is less than 7.8 mmol ሺ/l, and the content of 2 hours is in the range of 7.8-11.1 mmol/l Normal glucose tolerance determine if the content of glucose, and the content of 2 hours is less than 7.8 mmol/L.

Most people do not suffer from diabetes and have a normal glucose tolerance. In some of these people in the future there is a risk of reduced glucose tolerance and/or diabetes. One just confirmed risk factor is obesity, which is a moderate insulin resistance is a common phenomenon. This is often compensated in the fat body increased levels of insulin in plasma. However, the body is able to increase insulin secretion only to a certain level, so if insulin resistance in obese individuals continues to worsen, eventually the body will be unable to compensate due to the increased secretion of insulin. From this time, the content of glucose in the plasma will start to increase, representing a IGT or insulin-independent diabetes mellitus (NIDDM).

Obviously, this gradual deterioration in the direction of occurrence of IGT and NIDDM is undesirable for the health of the individual, and from the point of view of the high cost of treatment. Thus, it would be preferable to limit niospray the resistance to insulin in these individuals for as long as possible.

The term "glucose tolerance" includes glucose starvation in muscle tissue and the secretion of glucose by the liver.

The term "insulin resistance" means a reduced biological response to insulin. Insulin resistance may include effects on the secretion of glucose by the liver and peripheral capture glucose, and may be due to the reduced number of insulin receptors, lower tyrosinekinase activity of the insulin receptor and/or anomalies that are not associated with receptors.

Unexpectedly, it was found that the introduction of certain arylcyclohexylamines effectively reduces insulin resistance.

In accordance with the present invention, a method for reducing resistance to insulin in individuals who have not had reduced glucose tolerance and insulin-independent diabetes, but have an increased risk of developing such conditions, and this method includes the introduction to the needy in the human therapeutically effective amounts of compounds of formula I

including its enantiomers and pharmaceutically acceptable salts, where R1and R2independently represent hydrogen or methyl, in combination with a pharmaceutically acceptable diluent or carrier. the ne may be obese or non-obese individuals.

The preparation and use of compounds of formula I, such as N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine (or N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N,N-dimethylamine) and their salts in the treatment of depression described in the description of the patent in the UK 2098602. The use of compounds of formula I, such as N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine and its salts in the treatment of Parkinson's disease is described in European patent number 282206. The use of N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine and its salts in the treatment of functional disorders of the brain described in U.S. patent 4939175. The use of N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyraldehyde in the treatment of obesity are described in European patent number 397831. Especially preferred form of this compound is N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyronitrile monohydrate (sibutramine hydrochloride monohydrate), which is described in European patent number 230742. The use of N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine and its salts for improved resistance to insulin in patients with reduced glucose tolerance and insulin-dependent diabetes mellitus, is described in the publication mezhdunarodnoi application WO 95/20949. It is not described or not it is expected that the compounds according to the invention possess the insulin-sensitizing activity, and it is not described or not it is expected that the compounds according to the invention will be able to reduce insulin resistance in individuals who do not have IGT and NIDDM.

For professionals in this field may be valuable that the compounds of formula I may exist as salts of pharmaceutically acceptable acids. Examples of such acids include hydrochloride, hydrobromide, sulphates, methansulfonate, nitrates, maleate, acetates, citrates, fumarate, tartratami [for example, (+)-tartratami, (-)-tartratami or mixtures thereof, including racemic mixtures], succinate, benzoate and salts of amino acids such as glutamic acid. The compounds of formula I and their salts may exist in the form of a solvate (e.g. hydrate).

For professionals in this field may be valuable that the compounds of formula I may contain a chiral center. When the compound of formula I contains one chiral center, it may be in two enantiomeric forms. The present invention includes the individual enantiomers and mixtures of enantiomers. Enantiomers can be separated in accordance with techniques known to experts in this field, for example by formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation of diastereomer the different derivatives, that can be divided, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or recovery, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example, with a chiral stationary phase, for example, on silica gel with bound chiral ligand or in the presence of a chiral solvent. Interesting that if the desired enantiomer is converted into another compound during one of the above described methods for the extraction, a further step is necessary to highlight the desired enantiomeric form. Alternatively, the individual enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to another using asymmetric transformation.

Individual compounds of formula I are N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine, N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N,N-dimethylamine and 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine, including the racemates, individual enantiomers, mixtures thereof and the x pharmaceutically acceptable salt. The preferred compound of the formula I are N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine or its salt such as hydrochloride. The preferred form of this hydrochloride is monohydrate.

The compound of the formula I can be entered in any known pharmaceutical dosage form. The amount subject to the introduction of the connection will depend on a number of factors, including the patient's age, severity of the condition and medical history of the patient, and always lies within the competence of the attending physician, but provides that, as a rule, the dosage to be introducing the compound will be in the range from 0.1 to 50 mg, preferably from 1 to 30 mg per day, administered in one or multiple doses.

The preferred compositions for use according to the invention are oral dosage forms, and they are the known pharmaceutical forms for such administration, for example tablets, capsules, granules, syrups and aqueous or oil suspensions. The fillers used to obtain the data of the songs are fillers known in the pharmaceutical field. Tablets can be prepared from a mixture of active compounds with extenders, for example with calcium phosphate; with disintegrators, such as corn starch; lubricating agents, for the example with stearate; with binders, for example, microcrystalline cellulose or polyvinylpyrrolidone, and other optional ingredients known in the field, allowing the tablet mixture in accordance with known techniques. If desired, the tablets may be coated using known methods and fillers, which may include intersolubility floor, using, for example, phthalate of hydroxypropylmethylcellulose. Tablets can be prepared by known experts in the field of the way so that to ensure the long-releasing compounds according to the invention. If desired, such tablets can be equipped with intersolubility coatings in accordance with known methods, for example by applying acatitla cellulose. Similarly, in accordance with known techniques may be prepared with capsules, for example hard or soft gelatin capsules, containing the active compound with or without added fillers and, if desired, in a known manner provided with intersolubility coatings. The contents of the capsules can be prepared using known methods in such a way as to ensure the long-term release of the active compounds. Tablets or capsules may for convenience be contain from 1 to 50 mg of the active connections each.

Other dosage forms for oral administration include, for example, aqueous suspensions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent such as carboxymethyl cellulose, and oily suspensions containing a compound according to the invention in a suitable vegetable oil, such as peanut oil. The active compound may be incorporated into granules with or without added fillers. Granules can be directly ingested by the patient or they can be added to a suitable liquid carrier (e.g. water) before swallowing. Granules can contain disintegrant, for example effervescent couple formed by the acid and the carbonate or bicarbonate to aid in dispersion in a liquid medium.

Therapeutically active compounds of formula I can be included in the composition, which the patient holds in his mouth, so that the active compound was administered through the mucous membrane of the mouth.

Dosage forms suitable for rectal administration, are the known pharmaceutical forms for such administration, such as suppositories based on coconut oil or polyethylene glycol.

Dosage forms suitable for parenteral administration, are known pharmaceutical forms for such is edenia, for example sterile suspensions or sterile solutions in a suitable solvent.

Dosage forms for topical application can include the framework in which the pharmacologically active compounds according to the invention dispersed in such a way that the compounds are in contact with the skin for transdermal administration of compounds. A suitable composition for the transdermal injection can be prepared by mixing the pharmacologically active compound with the local media, such as mineral oil, petrolatum and/or wax, such as paraffin wax or beeswax, together with potential accelerator transdermal administration, such as dimethylsulfoxide or propylene glycol. Alternatively, the active compounds may be dispersed in a pharmaceutically acceptable basis for cream, gel or ointment. The number of active compounds contained in the composition for local application, must be such that during the period of time during which the composition for topical application applied on the skin, was delivered therapeutically effective amount of the compounds.

Therapeutically effective compound of the formula I can be incorporated into the composition that is sprayed in aerosol form into the oral or nasal cavity of the patient. Such aerosols may be introduced from a cylinder to pump the sludge is from a container under pressure, containing volatile propellant is used.

Therapeutically effective compounds of formula I can also be given by continuous infusion either from an external source, for example, by intravenous infusion, or from a source connection located inside the body. Internal sources include implanted reservoirs containing subject infusion connection, which is continuously released, for example, by osmosis, and implants, which may constitute (a) a liquid, such as oil suspension subject to infusion compounds, for example, in the form of very low water-soluble derivative such as dodecanoic or lipophilic ester, or (b) a solid substance in the form of an implanted substrate, for example, from a synthetic polymer or wax-like substances, to be infusion connection. The substrate can be a single body that contains all of the connection or series of bodies, each contains subject delivery connection. The number of active connections in the internal source should be such that over an extended period of time was delivered therapeutically effective amount of the compounds.

Some of the best compositions may be the use of compounds according to the invention in the form of particles of very small size is a, for example, those obtained using the water-jet mill.

In the compositions according to the invention, the active compound may, if desired, be associated with other compatible pharmacologically active ingredients.

Subsequent tests in vitro and in vivo confirmed that the compounds of formula I are effective in reducing insulin resistance and may have insulin-sensitizing effects. The specialist in this area will be valuable that 10 mg of sibutramine in the form of the hydrochloride monohydrate equivalent of 8.37 mg of sibutramine in the form of free base.

Study 1 - L6 muscle cells in vitro

Muscle L6 cells were obtained from European Culture Collection (Porton Down) and used at passages 7-11. Cells were maintained on standard medium for tissue culture medium DMEM, and glucose consumption was assessed using [3H]-2-desoxyglucose (DG) with or without added insulin (10-8M), as previously described (Walker PS, et al., Glucose transport activity in L6 muscle cells is regulated by the coordinate control of subcellular glucose transporter distribution, biosynthesis, and reduced mRNA, JBC, 1990; 265(3), 1516-1523, and Klip A, et al., Stimulation of hexose transport by metformin in L6 muscle cells in culture. Endocrinology, 1992; 130(5), 2535-2544).

Consumption DG expressed as percentage change compared with control. Values are expressed as mean ± SOS in series of 4 wells per experiment. The differences between the series of holes was evaluated with p the power of t-test Student, probability values of p<0.05 is considered significant. In the absence of added insulin in L6 cells, incubated for 24 hours with the compound of the formula I, in which R1and R2represent H, showed a significant increase in consumption DG (from 100±2,1 in controls to 116,9±3,8, 123,9±4.3 and 134±7,3 at 10-8, 10-7and 10-6M, respectively). In the presence of added insulin (10-8M) observed a significant increase in consumption TG after 24-hour incubation with the compound of the formula I, in which R1and R2represent methyl, (sibutraminehydrochlo monohydrate) at 10-8M (149,9±4.3 to 165,3±2,6), with the compound of the formula I, in which R1represents a methyl, a R2represents H, with 10-7M (147,3±3.0 to 160,7±4.5) and with the compound of the formula I, in which R1and R2represent H, with 10-7M and 10-6M (149,1±3.9 to 161,8±3.3 and 165,2±3,6, respectively).

This study shows that, in the presence or in the absence of added insulin compounds of formula I increase the consumption of glucose by muscle cells L6.

Study 2 - in mice ob/ob in vivo

Studies conducted on obese mice ob/ob (Aston Strain), which represent a model of severe resistance to insulin and also suffer from hyperglycemia. P is kishorganj and characteristics of this animal model have been previously described (Flatt PR, Bailey CJ, Development of glucose intolerance and impaired plasma insulin response to glucose in obese hyperglycaemic (ob/ob) mice, Horm. Metab. Res. 1981; 13: 556-560, and Bailey CJ et al., Influence of genetic background and age on the expression of the obese hyperglycaemic syndrome in Aston ob/ob mice. Int. J. Obesity, 1982; 6: 11-21). Mice ob/ob individually placed in cages made of polypropylene at a temperature of 21±1°C and 55% humidity. Mice had free access to standard pellets feed for rats and mice (Compound Rat and Mouse Diet, Special Diet Services, Witham, Essex) and tap water at any time. Animals were kept in a reverse light-dark cycle. The lighting was switched off between 09.00 hours and 17.00 hours in the acute experiment and between 10.00 and 18.00 h in the chronic experiment. At this time the laboratory was illuminated by red lights. Animals acclimatized to these conditions for at least two weeks before the start of the experiment. All animals within 7 days gave deionized water (at the beginning of the dark time). Daily measured body weight and food consumption. Directly before the daily introduction of media (deionized water 10 ml/kg p/o) or the compounds of formula I, where R1and R2represent methyl, (sibutraminehydrochlo monohydrate; 10 mg/kg p/o) for 1 day (control) and after 14 and 28 days of treatment (day 15 and 29 days, respectively) were taken blood samples. Blood samples also were collected 14 days after cancellation sibutraminewith orida monohydrate (43 day of the study). The content of glucose in the plasma was determined by glucose oxydase method (Analox GM7) and the content of insulin in plasma was determined by radioimmunoassay analysis (Amerlex, Amersham).

Between the values of body weight and food consumption after the introduction of media and sibutraminehydrochlo monohydrate significant differences were observed. The content of glucose in plasma ob/ob processed by sibutraminehydrochloride73.s monohydrate, decreased after 14 and 28 days of treatment with a significant difference from the control at 28 days (p<0,01, see table 1). Through 14 days after discontinuation of the medicinal product the concentration of glucose in plasma remained unchanged in the group treated with the carrier, but significantly increased in the group treated sibutraminehydrochlo monohydrate compared to control values. The values of the content of insulin in the plasma of significant changes were observed, although the content of insulin in plasma fell in the group treated sibutraminehydrochlo monohydrate and increased when cancelling the connection.

Study 3 - in mice ob/ob in vivo

Young mice ob/ob (Aston Strain) was randomly divided into 3 groups as follows: control, treated with placebo (phosphate-buffer solution, 2.5 ml/kg/day p/o); processed sibutraminehydrochlo monohydrate (5 mg/kg/day p/o); and a control with duplicate diet, get their same daily diet, that and consumed by animals from the group of processed sibutraminehydrochlo monohydrate, eve. The period of transition lasted for 1 week, followed 6 weeks of treatment. Every 1-2 days monitored body weight and food consumption, and blood samples for determination of glucose and insulin in plasma was collected from the tail vein at weekly intervals not on an empty stomach at 11 o'clock. After 5 weeks of treatment was performed in a/b test for tolerance to glucose (D-glucose, 2 g/kg in 40% (wt/V) solution in distilled water) and test for insulin-induced hypoglycemia (Actrapid, Novo-Nordisk, 2.5 U/kg/b). Food was not given only for the duration of these tests (approximately 4 hours). The selection of the control blood samples and test methods was performed 18 hours after the last injection of the drug.

Treatment was stopped after 6 weeks and the mice were observed over the next 6 weeks. Mouse with duplicate diet continued to receive the duplicate diet compared to the diet of animals from groups with cancellation of sibutraminehydrochlo monohydrate. The second test to insulin-induced hypoglycemia was performed 4 weeks after treatment was discontinued. The content of glucose in the plasma was determined by an automated glucose oxydase method (Beckman), and the content of insulin in plasma was determined by RA is immunome analysis (Amerlex, Amersham). During treatment sibutraminehydrochloride73.s monohydrate was observed a significant reduction of body weight and the content of insulin in the plasma compared with group processing media. In a/b test on glucose tolerance was observed a significant decrease in the content of insulin in plasma (p<0,05; see figure 1) and glucose in plasma (p<0,05; see figure 2) in the treatment of sibutraminehydrochloride73.s monohydrate compared with group processing media. In the test for insulin-induced hypoglycemia also showed a significant improvement (p<0,05; see figure 3; 5 weeks) in the treatment of sibutraminehydrochloride73.s monohydrate compared with group processing media. These results show that the compounds of formula I in relatively low dosages capable of improving sensitivity to insulin, because an improved glucose disposal with less insulin. Group

duplicate diet showed similar weight loss with group treatment sibutraminehydrochloride73.s monohydrate, but improvements in oral test glucose tolerance was not observed. Thus, the group with duplicate diet did not show improvement in sensitivity to insulin.

During the cancellation period of sibutraminehydrochlo monohydrate weight the content of insulin in the plasma remained significantly lower compared with group processing by the media during the entire 6-week cancellation period.

In table and figure 1-3 "sibutramine" means "sibutraminehydrochlo monohydrate".

Data obtained during these three studies show that the compounds of formula I are able to enhance as a background, and insulin-stimulated glucose consumption L6 muscle cells and in the absence of changes in either body weight or food consumption of the compound of the formula I, in which R1and R2represent methyl, are able to reduce the glucose content in the blood plasma of mice ob/ob. These data, taken together into account, assume the insulin-sensitizing effect of the compounds of formula I. the Data also show the ability of compounds of the formula I to reduce insulin resistance.

There are several syndromes, such as black acanthosis syndrome Donahue, lipoatrophy and polycystic ovarian syndrome, in which insulin resistance is manifested as part of their simptomokomplekse. The above data suggest that the compound of the formula I can be used to reduce the resistance to insulin in patients suffering from these conditions. Thus, the present invention provides a further application of the compounds of formula I in the manufacture of a drug product to reduce resistance to insulin in patients who Arnim by acanthosis, syndrome Donahue, lipoatrophy or polycystic ovarian syndrome or other conditions in which there is a resistance to insulin.

The present invention also provides a method of treating black acanthosis syndrome Donahue, lipoatrophy or polycystic ovary syndrome or other conditions where there is insulin resistance, comprising introducing the compound of formula I in combination with a pharmaceutically acceptable diluent or carrier to the needy in this patient.

Patients suffering from NIDDM, often treated with oral means, stimulating insulin secretion, such as 1,1-dimethyl-2-(2-morpholinoethyl)guanidinium (BTS67582) or sulfonylureas, including tolbutamide, tolazamide, hlorpropamid, glibenclamide, glimepiride, glipizide and gliclazide, or insulin-sensitizing means, including Metformin, ciglitazone, troglitazone and pioglitazone. Further application of the compounds of formula I in the manufacture of a drug for combination therapy of patients suffering from NIDDM, to normalize their body weight and symptoms of diabetes includes the compound of formula I, oral remedy stimulating insulin secretion, or insulin-sensitizing agent.

The present invention also provides a method normalizes and body weight and symptoms of diabetes in patients suffering from NIDDM, including the introduction of the compounds of formula I in combination with an oral agent that stimulates the secretion of insulin, or the insulin-sensitizing agent in combination with a pharmaceutically acceptable diluent or carrier to the needy in this patient.

Preferably, the oral agent that stimulates insulin secretion represents a 1,1-dimethyl-2-(2-morpholinoethyl)guanidinium (BTS-67582) or a sulfonylurea selected from tolbutamide, tolazamide, chlorpropamide, glibenclamide, glimepiride, glipizide and gliklazida.

Preferably, the insulin-sensitizing agent selected from Metformin, ciglitazone, troglitazone and pioglitazone.

The compound of formula I and oral means of stimulating insulin secretion, or insulin-sensitizing agent may be introduced either sachetana or competitive, for example, in the form of a discrete dosage forms, be simultaneous, separate or sequential use. Accordingly, the present invention also provides a product containing a compound of the formula I and oral means of stimulating insulin secretion, or insulin-sensitizing agent, as a combined preparation for simultaneous, separate or sequential use for the normalization of body weight and eliminate the symptoms of diabetes in patients suffering from NIDDM. The content of the compounds of formula I and the content of oral contraceptives, stimulating insulin secretion, or insulin-sensitizing agents is such that the amount of each of the applied active ingredient was therefore to provide a therapeutically effective level, but will not be higher than the number recommended for safe use.

The action, which consists in reducing resistance to insulin, shown by the compounds of formula I shows that the compounds of formula I can be applied in the manufacture of a medicinal product, which can be used as insulin-sensitizing means. Accordingly, the present invention also provides the use of compounds of formula I in the manufacture of a medicinal product, which is an insulin-sensitizing agent.

Some patients who have been diagnosed with insulin-dependent diabetes mellitus, also may be a certain level of immunity to insulin. Thus, the best may be the treatment of these patients with the compounds of formula I to reduce their resistance to insulin. This will mean that these patients will require lower doses of insulin to maintain symptoms of Sakha the aqueous diabetes at the same or better level, because the insulin dose would be associated with greater efficiency to reduce glucose in the blood. This therapy will provide long-term improvement in reducing the harmful effects that may be caused by prolonged treatment with high doses of insulin. In addition, some patients suffering from NIDDM, also get treatment with insulin and have insulin resistance. Accordingly, the present invention also provides a method and use of the compounds of formula I in the manufacture of a drug product to reduce the amount of insulin required daily person suffering from insulin-dependent diabetes mellitus or NIDDM. Accordingly, the present invention also provides a method and use of the compounds of formula I in the manufacture of a medicinal product for the prevention of long-term harmful effects caused by prolonged treatment with high doses of insulin persons suffering from insulin-dependent diabetes mellitus or NIDDM.

1. The method of reducing resistance to insulin in people who do not have reduced glucose tolerance and non-insulin dependent diabetes mellitus (NIDDM), but who have an increased risk of developing such conditions, characterized in that it includes an introduction to the needy in this human a therapeutically effective amount the VA compounds of formula I

including its enantiomers and pharmaceutically acceptable salts, where R1and R2independently represent hydrogen or methyl, in combination with a pharmaceutically acceptable diluent or carrier.

2. The method according to claim 1, characterized in that the man is not fat.

3. The method according to claim 1, characterized in that the man is fat.

4. The method according to any preceding paragraph, wherein the compound of formula I is N,N-dimethyl-1-[1-(4-chlorophenyl)-cyclobutyl]-3-methyl-butylimidazole.

5. The method according to any preceding paragraph, wherein the compound of formula I is N,N-dimethyl-1-[1-(4-chlorophenyl)-cyclobutyl]-3-methyl-butylimidazole in the form of a monohydrate.

6. The use of the compounds of formula I

including its enantiomers and pharmaceutically acceptable salts, where R1and R2independently represent hydrogen or methyl, as a means to reduce insulin resistance in people who do not have reduced glucose tolerance and non-insulin-dependent diabetes, but who have an increased risk of developing such conditions.

7. The use according to claim 6, in which man is not fat.

8. The use according to claim 6, wherein the individual I who is fat.

9. Use PP, 7 or 8, wherein the compound of formula I is N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methyl-butylamine hydrochloride.

10. Use PP, 7 or 8, wherein the compound of formula I is N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine hydrochloride in the form of a monohydrate.

11. The use of pharmaceutical compositions comprising a therapeutically effective amount of the compounds of formula I

including its enantiomers and pharmaceutically acceptable salts, where R1and R2independently represent hydrogen or methyl, in combination with a pharmaceutically acceptable diluent or carrier as a means to reduce insulin resistance in people who do not have reduced glucose tolerance and non-insulin-dependent diabetes, but who have an increased risk of developing such conditions.

12. The application of claim 11 in which the compound of formula I is N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methyl-butylimidazole.

13. The application of claim 11 in which the compound of formula I is N,N-dimethyl-1-[1-(4-chloro-phenyl)cyclobutyl]-3-methyl-butylimidazole in the form of a monohydrate.

14. The use of the compounds of formula I as insulinsensitizing tools.

15. The application is soedineniya formula I as a means to reduce the amount of insulin, daily desired person suffering from insulin-dependent diabetes mellitus or NIDDM.

16. The use of the compounds of formula I as a means for prevention of late effects caused by prolonged treatment with high doses of insulin persons suffering from insulin-dependent diabetes mellitus or NIDDM.

17. The use of the compounds of formula I as a means to prevent low glucose tolerance and non-insulin-dependent diabetes in people who have an increased risk of their development.

18. The application 17, in which man is not fat.

19. The product containing the compound of the formula I and oral means of stimulating insulin secretion, or insulinsensitizing means in the form of a combined preparation for simultaneous, separate or sequential use for the normalization of body weight and symptoms of diabetes in patients with NIDDM.

20. The product according to claim 19, in which oral agent that stimulates insulin secretion represents a 1,1-dimethyl-2-(2-morpholinoethyl)guanidinium (BTS-67582) or a sulfonylurea selected from tolbutamide, tolazamide, chlorpropamide, glibenclamide, glimepiride, glipizide and gliklazida.

21. The product according to claim 19, in which insulinsensitizing means selected from Metformin, qi is glitazone, troglitazone and pioglitazone.

22. The product containing pharmaceutical composition that includes a compound of formula I and oral means of stimulating insulin secretion, or insulinsensitizing tool in combination with a pharmaceutically acceptable diluent or carrier.

23. The product according to item 22, in which oral agent that stimulates insulin secretion represents a 1,1-dimethyl-2-(2-morpholinoethyl)guanidinium (BTS-67582) or a sulfonylurea selected from tolbutamide, tolazamide, chlorpropamide, glibenclamide, glimepiride, glipizide and gliklazida.

24. The product according to item 22, in which insulinsensitizing means selected from Metformin, ciglitazone, troglitazone and pioglitazone.

25. The way to reduce the amount of insulin required daily person suffering from insulin-dependent diabetes mellitus or NIDDM, characterized in that it includes the introduction of the compounds of formula I in combination with a pharmaceutically acceptable diluent or carrier needs this man.

26. The way to prevent long-term effects caused by prolonged treatment with high doses of insulin persons suffering from insulin-dependent diabetes mellitus or NIDDM, characterized in that it includes the introduction of the compounds of formula I in combination with a pharmaceutically acceptable diluent or carrier is in need of this person.

27. The method according to p, in which man is not fat.

28. The way to prevent low glucose tolerance and non-insulin-dependent diabetes in people who have an increased risk of their development, characterized in that it includes the introduction of the compounds of formula I in combination with a pharmaceutically acceptable diluent or carrier needs this man.



 

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where: R represents hydrogen;

-ORawhere Rarepresents hydrogen, alkyl, phenyl or alkylphenyl;

-NRaRbwhere Raand Rbare the same or different and represent hydrogen, alkyl, phenyl, alkylphenyl, cyano;

R1represents alkyl, cyano;

-ORewhere Rerepresents alkyl, phenyl or alkylphenyl;

-O-(CH2]m-ORfwhere Rfrepresents alkyl, and m is an integer of 1-2;

-SRdwhere Rdrepresents an alkyl or phenyl;

-SO2ORawhere Rarepresents alkyl, phenyl or alkylphenyl;

-COORdwhere Rdrepresents alkyl;

R2represents hydrogen or alkyl;

R3and R4

D is situated in the ortho-, meta - or para-position and represents a

-OSO2Rdwhere Rdrepresents alkyl, phenyl or alkylphenyl;

-OCONRfRawhere Rfand Rarepresent hydrogen, alkyl, phenyl or alkylphenyl;

-NRcCOORdwhere Rcrepresents hydrogen or alkyl and Rdrepresents alkyl, phenyl or alkylphenyl;

-NRcCORawhere Rcrepresents hydrogen or alkyl, and Rarepresents hydrogen, alkyl, phenyl or alkylphenyl;

-NRcRdwhere Rcand Rdrepresent hydrogen, alkyl, phenyl or alkylphenyl;

-NRcSO2Rdwhere Rcrepresents hydrogen or alkyl, and Rdrepresents alkyl, phenyl or alkylphenyl;

-NRcCONRaRkwhere Rcrepresents hydrogen, Raand Rkare the same or different and each represents hydrogen, alkyl, phenyl or alkylphenyl;

-NRcCSNRaRkwhere Rcrepresents hydrogen, Raand Rkare the same or different and each represents hydrogen, phenyl иLASS="ptx">-SRcwhere Rcrepresents alkyl, phenyl or alkylphenyl;

-SO2ORawhere Rarepresents alkyl, phenyl or alkylphenyl;

-CN;

-CONRcRawhere Rcrepresents hydrogen or alkyl, and Rarepresents hydrogen or alkyl;

D’ is located in the meta-position and represents-ORfwhere Rfrepresents alkyl; or is located in the ortho-, meta - or para-position and represents hydrogen;

D’ is located in the ortho - or para-position and represents-NO2, -ORfwhere Rfrepresents alkyl; or is located in the ortho-, meta - or para-position and represents hydrogen;

where specified, the alkyl means a straight or branched alkyl group having from 1 to 6 carbon atoms, or cyclic alkyl having from 3 to 6 carbon atoms, with the specified alkyl may be substituted by one or more than one group of alkyl, alkoxy, halogen or phenyl; where the specified phenyl may be substituted by one or more than one group of alkyl, alkoxy, nitro, thiol, or halogen; the invention also relates to a method of their production, pharmaceutical preparations containing them, the Sabbath.

The invention relates to new pharmaceutical compositions that contain the basis or agonist of the basis for the treatment of diabetes, slowing of gastric emptying or reduce food intake, and their dosage forms and methods for their introduction
The invention relates to medicine, Hematology, cardiology and endocrinology and can be used for normalization of platelet aggregation in patients with metabolic syndrome

The invention relates to water-soluble unit derived insulin, which remains In 24-B30 of the b-chain derived insulin is sequence Phe-x-X-x-X-x-X, where each X independently represents any amino acid or a deletion of at least one X is Nsubstituted by a lysine residue in which the Deputy is a 5--lithocholic acid or 5--lithocholic acid, connected through the-glutamyl,-glutamyl oror-aspartyl as a linker, where the unit size is defined in the gel-filtration system, more than aldolase, and the Assembly includes at least 2 zinc ions per 6 molecules derived insulin

Glp-1 derivatives // 2214419
The invention relates to a derivative of GLP-1 parent peptide having one or two lipophilic substituent attached optionally via an amino acid or dipeptide spacer to amino acid residue that is not N-terminal or C-terminal amino acid residue, where the parent peptide has the sequence: HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG, or is in the amount of up to ten amino acid residues are replaced with any-amino acid residue which can be encoded using the genetic code
The invention relates to medicine, in particular to surgery, and can be used for the surgical treatment of diabetes

The invention relates to a method for producing the precursor of insulin or insulin derivatives with properly connected cystine bridges in the presence of cysteine or testingground and chaotropes excipients, characterized in that the following steps performed in sequence: (a) mixing the aqueous slurry of the precursor of insulin or insulin derivatives with a number of cysteine or testingground, which gives up to 15 SH-cysteine residues or testingground one cysteine residue of the precursor, (b) the introduction of cysteine or containsignorecase suspension predecessor in 4-9-molar solution chaotropes excipients when the pH value of 8 to 11.5 and a temperature of 15 - 55oWith, keeping the mixture for 10-60 min at this temperature and (b) introducing the mixture at a pH value of 8 to 11.5 and a temperature of 5 to 30oWith the amount of water, which gives a dilution of the concentration of cysteine or testingground in a mixture of 1-5 mm and chaotropes excipients 0.2-1.0 M

The invention relates to medicine

The invention relates to zinc-containing crystals of insulin, which has a diameter less than 10 microns, suitable for introduction through the lungs

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes new tablets with size less 3 mm with sustained-releasing the opioid analgesic drug for 30 min in the amount above 75%. Invention provides opioid for oral intake with taking into account individual necessity of patient due to selection of required amount of mictotablets by dispenser.

EFFECT: valuable properties of tablet, expanded assortment of medicinal formulations of opioid analgesics.

19 cl, 4 tbl, 4 ex

FIELD: medicine, anesthesiology, resuscitation.

SUBSTANCE: one should perform puncturing of epidural space at Th12-L1 level. Through the lumen of puncture needle one should introduce catheter to move it cranially at the depth of 3 cm. After that one should inject 10 ml 05%-marcaine solution to perform repeated injections per 5.0 ml every 4 h during 1-8 d. The effect is achieved due to unloading minor cycle of circulation.

EFFECT: higher efficiency of therapy.

2 ex

The invention relates to pharmaceutical

The invention relates to medicine and can be used in the treatment of musculoskeletal disorders of the larynx caused by damage to the recurrent nerve

A therapeutic agent // 2234917
The invention relates to medicine, to a method of treating obesity in a human in need of such treatment, by appointing such a person a therapeutically effective amount of the compounds of formula I, including enantiomers and pharmaceutically acceptable salts, where R1and R2independently mean hydrogen or methyl, and therapeutically effective amounts of compounds of formula II, in which the compound of formula I and the compound of formula II appointed simultaneously, separately or sequentially, and farbkomposition, including the compounds of formula I and II

The invention relates to possess analgesic activity of new substituted Cycloheptane General formula I

in which R1IT denotes, O-C1-C6alkyl, R2represents C1-C6alkyl, (CH2)(1-2)-aryl, and R3means (CH2)(0-1)-C5-C7cycloalkyl, (CH2)(0-2)-aryl, and the rest of the aryl can be substituted one or more times, HE, F, Cl, CF3C1-C6the alkyl, in the form of their racemate or enantiomer, in the form of bases, and salts physiological acceptable acids

The invention relates to the field of medicine and relates to new derivatives colchisol with property damage blood vessels, which can find application in the treatment of tumors

FIELD: medicine, anesthesiology, resuscitation.

SUBSTANCE: one should perform puncturing of epidural space at Th12-L1 level. Through the lumen of puncture needle one should introduce catheter to move it cranially at the depth of 3 cm. After that one should inject 10 ml 05%-marcaine solution to perform repeated injections per 5.0 ml every 4 h during 1-8 d. The effect is achieved due to unloading minor cycle of circulation.

EFFECT: higher efficiency of therapy.

2 ex

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