Method of obesity treatment

FIELD: medicine.

SUBSTANCE: preparations Zonisamide and Bupropion are used in combination.

EFFECT: provides effective weight reduction due to synergetic effect of these preparations on organism.

7 cl, 4 ex, 2 dwg, 1 tbl

 

This application claims priority to provisional application No. 60/380874, filed may 17, 2002, the contents of which are incorporated here by reference.

The scope to which the invention relates.

The present invention relates, in General, to obesity, in particular to a method of treating obesity and minimize the associated metabolic risk factors by using, for example, zonisamide or otherwise promotes weight loss anti-convulsants, single or in combination with bupropion or other compound that enhances the activity of norepinephrine and/or dopamine via suppression of absorption and/or another mechanism.

The level of technology

The prevalence of obesity has increased significantly in the last decade in the United States and many other developed countries (Fiegal et al., Int. J. Obesity 22: 39-47 (1998), Mokdad et al., JAMA 282: 1519-1522 (1999)). Because obesity is associated with significantly increased risk for type 2 diabetes, coronary cordial disease, hypertension and many other important diseases and overall mortality from all causes (Must et al., JAMA 282: 1523-1529 (1999), Calle et al, N. Engl. J. Med. 341: 1097-1105 (1999)), weight loss is critical for fat patients (Blackburn, Am. J. Clin. Nujtr. 69: 347-349 (1999), Galuska et al., JAMA 282: 1576 (1999)). There is important evidence that pharmacotherapy may enhance weight loss when combined with interventions aimed at changing lifestyle (National Heart, Lung and Blood Institute, Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults: the evidence report of Clinical guidelines on the identification, evaluation and treatment of overweight and obesity in adults: the evidence report, NIH Publication No.98-4083, Sept. 1998). Still available pharmacological therapies for relief of weight loss are not able to provide adequate success for many obese patients due to side effects, contraindications or absence of a positive reaction (National Heart, Lung and Blood Institute, Clinical guide-lines on the identification, evaluation, and treatment of overweight and obesity in adults: the evidence report of Clinical guidelines on the identification, evaluation and treatment of overweight and obesity in adults: the evidence report, NIH Publication No.98-4083, Sept. 1998). Therefore, there is an incentive to develop new and alternative therapies to deal with obesity.

Zonisamide (ZONEGRAN®) is released into the market of anti-epileptic medication (line) (AED). In short-term clinical trials zonisamide in epileptic patients taking other related line, a small percentage of patients showed a small degree of weight loss as an adverse effect (Oommen and Matthews, Clin. Neuropharmacol. 22: 192-200 (1999)). It is considered that the anticonvulsant activity of zonisamide related to its activity in blocking sodium and calcium channels, T-type (Oommen and Matthews, Clin. Neuropharmacol.22: 192-200 (1999)). It is also known that this medication shows dopaminergic (Okada et al., Epilepsy Res. 22: 193-205 (1995)), and dose-dependent biphasic serotonergic activity (Okada et al., Epilepsy Res. 34: 187-197 (1999)).

Topiramate (TORMACH®) is a line, which is demonstrated in the clinical trials of human epilepsy its effectiveness as adjunctive therapy in the treatment of simple and complex partial seizures and secondarily generalized seizures (Faught et al., Epilepsia 36 (S4): 33 (1995); Sachdeo et al., Epilepsia 36 (S4): 33 (1995)). At the present time it is released to the market as an additional treatment when initial partial seizures or primary generalized tonic-clonic seizures.

Bupropion has been on the market as an antidepressant, has a pharmacological effect, dissimilar to those in zonisamide or topiramate. It is shown that bupropion causes significant weight loss in patients, detecting primary obesity (Gadde et al., Obes. Res. 9 (9): 544 (2001)).

The present invention is based, at least in part, from studies demonstrating that zonisamide is more effective than placebo for weight loss in obese subjects. Using zonisamide (or other promoting weight loss anti-convulsants) and bupropion (or other composition, which increases the turnover of Manoa is in (for example, serotonin, norepinephrine and/or dopamine) in the brain by suppressing the absorption or other mechanism) provides effective treatment of obesity with low side effects.

Disclosure of inventions

The present invention relates in General to obesity. More specifically, the invention relates to a method for the treatment of obesity and minimize the associated metabolic risk factors by using, for example, zonisamide or otherwise promotes weight loss anti-convulsants, single or in combination with bupropion or other compound that enhances the activity of norepinephrine and/or dopamine via suppression of absorption and/or another mechanism.

Objectives and advantages of the present invention will be clear from the following description.

Brief description of drawings

Figure 1. The balance of the studied subjects.

Figure 2. The weight change graph from start to week 16 in obese subjects who took zonisamide (n=30) or placebo (n=30). The results constructed as the mean (SE). Data obtained from recent direct analysis of the performed observations (LOCF).

Detailed description of the invention

The present invention relates to a method of treating obesity in an animal. The invention further relates to a method of minimization of metabolic risk factors associated with obesity such as high blood pressure, d is the Abete and dyslipidemia. In one embodiment, the methods include the introduction of an animal in need of such treatment, an effective amount of zonisamide or other promoting weight loss anti-convulsants. In an alternative embodiment, the methods include the introduction, in effective amounts, a combination of zonisamide or topiramate, or other promoting weight loss anti-convulsants (including agents that block Kainat/AMPA glutamate receptors (D,L-a-amino-3-hydroxy-5-methyl-isoxazol propionic acid) subtype), and bupropion, or other compound that enhances the activity of norepinephrine and/or dopamine via suppression of absorption or other mechanism.

Preferred active agents for use in the present invention include zonisamide or topiramate (and their pharmaceutically acceptable salts, but other derivatives methanesulfonamide, such as described in U.S. patent No. 4172896, or other sulfamate (including sulfamethazine monosaccharides), such as described in U.S. patent No. 4513006, may also be used. Although the use of bupropion is also preferably can be used in the compositions disclosed in U.S. patent No. 3819706 and 3885046, as well as other compounds that increase the activity of norepinephrine and/or dopamine via suppression learned what I or other mechanism (for example, Atomoxetine or reboxetine).

As used here, the term "obesity" includes both excess body weight and excess fat tissue of the animal. Fat individual is such (for example, 21-50 years), which has a BMI >30 kg/m2.

Although the animal is usually a person, the invention encompasses the treatment and non-human mammals.

The number of input(s) active(s) agent(s) (for example, zonisamide one or in combination with, for example, bupropion) may vary depending on the patient, route of administration and the desired result. The optimal dose regimens for individual patients can be immediately found by experts.

When zonisamide is used alone, the dose may be from about 25 mg to about 800 mg per day, generally given once a day or divided (for example, equally divided) into multiple doses. Preferably, the dose is from about 100 mg to about 600 mg per day, more preferably from about 200 mg to about 400 mg per day.

However, it may be necessary to use dosages outside these ranges.

When using combination therapy, daily dose, for example, zonisamide can be from about 25 mg to about 800 mg, preferably from about 100 mg to about 600 mg, more preferably from about 200 mg of d is about 400 mg. When combination therapy is used topiramate daily dose of topiramate may be from about 25 mg to about 1600 mg, preferably from about 50 mg to about 600 mg, more preferably from about 100 mg to about 400 mg used Daily dose of bupropion may be from about 25 mg to about 600 mg, preferably from about 50 mg or about 150 mg to about 450 mg Dose can be given once daily or divided (for example, equally divided) into multiple doses. It may be necessary to use dosages outside these ranges. When using combination therapy, the ratio of zonisamide (or topiramate) to bupropion may be within, for example, from about 2:1 to about 1:2.

When using combination therapy, the individual components of the combination can be administered separately at different times during the course of therapy or concurrently in separate or common combinations.

In accordance with the present invention, the active(s) agent(s) (for example, zonisamide alone or in combination with bupropion) may be entered in any convenient manner, such as oral, sublingual, rectal, parenteral (including subcutaneous, razoblachenny, intramuscular and intravenous), or percutaneous. The most preferred route of administration is the oral route.

Act the main agents of the invention can be administered as pharmaceutical compositions or compositions, which contain one or both of the agent in a mixture with a pharmaceutical carrier. This pharmaceutical composition may be in the form of a dosage unit of the type of tablets, capsules, political, capsules, granules, powder, syrup, suppositories, injections or the like.

You can also use a supported release formulations. The composition can also be present in the transdermal delivery system, for example, skin the plaque.

Details of suitable routes of administration and compositions suitable for this purpose can be found in, for example, U.S. patents№ 6110973, 5763493, 5731000, 5541231, 5427798, 5358970 and 4172896, and the patents cited therein.

In accordance with the invention, the combination of, for example, zonisamide or topiramate and bupropion (including supported release formulation) is an effective treatment for obesity and provides an effective means of minimizing metabolic risks associated with obesity. This combination may be more effective than, for example, treatment with one zonisamide or topiramate and with fewer side effects.

Neuropharmacological all three large nerve transmitter that regulate appetite and weight, i.e. serotonin, norepinephrine, and dopamine, are the target of combination, such as bupropion and zonisamide or topiramate. Side effects, for example, zonisamide is or topiramate (type drowsiness, the slowing of psychomotor reactions, impaired cognitive abilities, fatigue and depression) can be compensated for insomnia, activation, stimulation of psychomotor reactions and antidepressant effects, such as bupropion. On the other hand, zonisamide or topiramate, for example, can lower the risk of seizure associated with, for example, bupropion. Lower doses of both types of drugs can be used in combination treatment, thereby further reducing the overall burden of side effects.

Some aspects of the invention are described in more detail in the following non-limiting examples and Gadde et al., JAMA 289: 1820 (2003). (See also U.S. patent No. 6323236, 6071537, 6548551, 6506799 and 6191117.)

Example 1

Details of the experiment

Subjects

Were selected sixty-eight subjects for participation, and 60 subjects were randomized.

Inclusion criteria were: male or female 21-50 years, with body mass index (BMI) (BMI) >30 kg/m2.

Exclusion criteria were: obesity of known endocrine origin, type of hypothyroidism and Cushing's syndrome; severe/unstable medical or psychiatric illness; current major psychiatric disorder; current use of a drug or alcohol; past or current renal disease or kidney stones; significant liver disease; n is controlled hypertension; current diabetes mellitus (DM) (DM) type 1 or 2 DM with receiving pharmacotherapy; untreated or uncontrolled disease of the thyroid gland; loss or weight gain of more than four pounds in the last three months; surgery of obesity in the past; current or recent use of any medications, herbs or supplements for weight loss; current or recent use of drugs, herbs or dietary supplements known as significantly affecting the weight of the body; concomitant medications that significantly affect microsolutions enzymes P450 3A4 liver; hypersensitivity to sulfonamides; a woman of childbearing age who do not follow the acceptable forms of contraception, pregnant or lactating women; and entities that are considered unable to follow the instructions and study procedures.

Analyzed project

The study had two phases. The first was an acute phase 16 weeks of randomized, double-sided blind, parallel-group comparison of zonisamide (ZON) and placebo (VBOs). This was accompanied by an optional 16-week phase of expansion. At the end of the acute phase subjects who wished to continue, received later the same treatment for an additional 16 weeks in a one-sided blind.

Randomization, dispensing and distribution of medications to

Subjects were randomized the ratio of 1:1, to get capsules zonisamide or placebo. The study medication was distributed blindly using a computer randomization. This randomization was generated using a random number table with a block size of ten. There was no classification at the genus or other demographics. The researchers did not know the "blocking" method used by the pharmacy. Codes for treatment were not available to researchers until all the objects have not completed the acute phase and no data has been entered and the database for this phase was locked, which means that no further changes in the data could not be made.

The study drug was distributed in the form of capsules. Each capsule contained 100 milligrams or zonisamide or placebo. Capsules were made so that they looked identical. Increase dose was as follows: one capsule (100 mg zonisamide or placebo) every night for the first 2 weeks; two capsules (200 mg zonisamide or placebo) every night for weeks 3 and 4; three capsules (300 mg zonisamide or placebo) every night for weeks 5 and 6; and, four capsules (400 mg zonisamide or placebo) every night from week 7 onwards. At week 12, the dose could be increased further up to six capsules (600 mg zonisamide or placebo) every evening for those subjects who did not lose at least 5% of their initial vesatile. If the subject chose not to take all six capsules at the same time, the option was receiving half of the daily dose in the morning. On the basis of the admissibility of increasing dose can be discarded, or the dose could be reduced. For compliance with taking medications was observed by recording the number of returned tablets and compared this number with the number of capsules given for each visit.

Recommendations on diet and lifestyle

Subjects in both treatment groups were instructed to follow an individual diet, which was 500 kcal/day less than the one in which they needed to maintain their weight.

Prescribed diet based on the consumption of various foods from the Food Guide Pyramid emphasizes the reduced portions, eating more fruits and vegetables and drink 8 cups of water each day.

Was also encouraged increased physical activity of the subjects in both groups. Subjects were asked to record their dietary intake, including portion sizes, diaries power, which they were supplied. Registered dietitian reviewed the diaries of power and provided guidance to all stakeholders. Subjects were encouraged to make healthy changes in their diets and physical activity, which could be maintained after completion of the study.

Visits and measurements

Sub the projects examined at weeks 0, 2, 4, 8, 12 and 16 in the acute phase and every four weeks in the phase of expansion. During each visit the following assessment: blood pressure, heart rate, weight, compliance with the diet, the possibility of accounting and tolerability of medications, adverse effects.

Body weight was measured on a calibrated electronic scale accurate to 0.1 kg. Registered dietitian reviewed the diaries of power and assessed compliance of the diet. Adverse effects was collected from spontaneous reports of subjects, and how do clinicians requests with open endings. Noteworthy adverse effects were new symptoms or diseases that have emerged in the course of treatment or who had an increase in severity compared to the basis.

In addition to the above, the subjects performed the impact of weight on quality of life (WKG) (IWQOL) (Kolotin et al., Obesity Res. 3: 49-56 (1995)) at the beginning of week 8 and week 16. WCG is smoothened measurement with 74 points, which assess the effect of weight on quality of life in the following areas (podskalak): health, social/interpersonal life, work, mobility, self-esteem, sexual life, activities of daily life and food (comfort food). Improvement in the treatment reflected a reduction of points on all podskalan for everyone is in podskalny food (comfort food), which, as expected, shows a smaller amount of comfort around the power with effective treatment. The body composition (fat and muscle) and bone mineral density (BMD) (BMD) was determined at the beginning and at week 32 measurement dual x-ray absorption (DXA; Hologic 2000, Waltham, MA). All DXA measurements were collected using the same equipment and methods. Subjects were instructed to fast for 8 hours and not drinking water or other beverages for at least 4 hours before measurement DXA.

Results and criteria outcome

Body weight was the main result. Check were the absolute change in weight, percent change in weight and the number of subjects in each group who achieved a weight loss of 5% and 10%. Secondary criteria of the included heart rate, blood pressure, frequency of adverse effects, electrolytes and lipids fasting, waist measurement, VAS-C, WKG, body composition and BMD.

Statistical analysis

All randomized subjects were included in the primary analysis. The alleged differences between the subjects in the group zonisamide compared with subjects in the placebo group were tested using t-test, t-test for continuous variables and Fisher's exact test for categorical joint random variables. The variable is dichotomous proximity denoting status, the dropout, also tested between groups using Fisher's exact test. Two subjects who refused after only the initial interview, were removed from further research.

Weight change during the study was assessed in terms of the actual weight in six intervals of the study using the methodology of multivariable regression and as a result, the dichotomy of reactions, i.e. weight loss of 5% at week 16 and weight loss of 5% and 10% at week 32. Variables vicinity, indicates the status of the reaction was checked on the conditions of treatment, again using Fisher's exact test. Conducted three studies of multivariable regression. In the first the body weight at each time point were analyzed using growth curve model with random effects. Heuristically, this model satises the linear regression for each subject using the available data points, thereby maximizing the use of valid data. For the second set of analysis the weight of the bodies were subjected to regression as above, with observations breaks, running forward from the last recorded weight based on the approach of the "intent to treat" (NL) (LOCF). The final model was limited to a subset of the correspondents with the data of the lack of breaks ("saperately"). All models included the covariance for the genus and MI, and proximity variables denoting the condition of treatment, time, and time for interaction with treatment over time; the age and percentage body fat at the beginning of practically were not associated with weight loss and, therefore, excluded from the above models.

Secondary analyses were performed on three General areas of interest. In each case, the research was based on 2×2 repeated measurements ANOVA, which include time, the state of the drugs and their interaction (time by medicine). The main interest in each case was determined whether there was an effect on the subjects in zonisamide otherwise relative to the control, as operationally defined impact by examining the significance of the estimated interaction term. Check in the first area of concern focused on clinical indicators, including levels of creatinine, glucose, triglycerides, lipoproteins, high and low density (all of them were evaluated at the beginning and at the end of the study), waist measurement (at the beginning of week 8 and week 16), blood pressure (systolic and diastolic) and heart rate.

The second General area of the test quality of life indicators, including the actions of everyday life, appetite, respect, health, interpersonal relationships, mobility, sex, and R is the bot using a scale WCG, repeated measurements were carried out at the beginning of week 8 and week 16. For the final set of secondary analyses were selected hunger and appetite using visual analog scales for hunger and craving for food. Selected categories included sweets, bread, salt, fats, meat, soda and General hunger. The measurements were carried out at the beginning of week 8 and week 16.

The frequency of a particular adverse effect was tested according to the terms of medicines using Fisher's exact test.

Results

Characteristics and arrangement of subjects

Of the 68 subjects selected for participation, 8 were unsuitable (Figure 1). Sixty subjects were randomized to 30 to get zonisamide (ZON) and 30 placebo (VBOs). Nine subjects - 6 in the group VBOs and 3 in the group ZON - dropped in the acute phase; thus, the first 16 weeks ended 51 of 60 subjects. Typical reasons for premature discontinuation were adverse events (ZON 1, VBOs 2), the vain pursuit (ZON 1, VBOs 2), the resolution on the refusal (ZON 0, VBOs 2) and Protocol violation (ZON 1, VBOs 0).

In regard to the characteristics of the subjects at the beginning (table 1) there was no significant difference between treatment groups with the following exceptions: in the distribution of the genus were critical difference (p=0,08), as all five men who in the study were randomized to ZON. Initial BMI was slightly lower (p=0.07) in the ZON group.

Table 1.
Initial characteristics of the subjects
DescriptionZonisamide (n=30)Placebo (n=30)
Age, years37,5 (1,3)36,4 (1,6)
Gender, number
Men50
Women2530
Race number
Black1217
White1813
Weight, kgof 98.2 (2,5)of 97.8 (2,6)
BMI, kg/m235,4 (0,7)37,2 (0,8)
Body fat, %40,8 (0,9)42,6 (0,8)

Age, weight, BMI and body fat are presented as group mean (SE).

BMI denotes body mass index, defined as weight in kilograms divided by the square of height in meters.

Presents first results of the acute phase (initial 16-week treatment), which was bilateral blind and included all randomized subjects. Since the phase of the EXT is tion was optional and unilaterally blind, all the important results of this phase are presented separately.

Dose

Prescribed higher average daily dose of zonisamide was 427 (29) mg, which corresponds 4,27 capsules, whereas the placebo group received 5.00 capsules (equivalent to 500 mg).

Weight loss

Percentage and absolute change in weight

Curves for weight change as a percentage weight loss in a 16-week duration for groups zonisamide and placebo are shown in figure 2 for subjects in the analysis of "intention to treat" (NL) (ITT with LOCF. Mean (SE) estimated weight loss for a group of zonisamide (n=30) was 5,98% (0,82%) compared to 1,02% (0,40%) for the placebo group (n=30); time x treatment interaction was significant (F1,58=22.05; p<0,0001). For the population ITT-LOCF absolute weight has changed for a group of zonisamide from 98,17 (2,5) kg in the beginning to 92,28 (2,47) kg at week 16, whereas for the placebo group, the corresponding change was from 97,75 (2,63) kg to 96,86 (2,78) kg (time x treatment: F1,58=24,65; p<0,0001). The results from the analysis of random regression coefficients were supported various weight loss for treated zonisamide subjects. Regardless of the prescribed procedures, the interaction of drugs over time was significantly different from zero in all models. For prescribed probabilistic model, the estimated regression coefficient associated with the term vzaimode istia, predicted weight loss in a week than 0.3 kg during the study; complementary values for the other two models were 0,29 kg/week using prescriptions with intent to be treated" LOCF and 0.21 kg/week, as estimated from the model based only on subjects with complete data. Among the remaining joint variables female gender was associated with significantly lower levels of scales, while the higher estimates of BMI were associated with increasing levels of scales, again regardless of the model.

For a subset of subjects completing the 16-week acute phase, the difference between treatment groups in the attained weight loss over time was again significant (F1,49=20,07; p<0,0001) weight loss 6,61% (0,81%) for ZON group compared with the loss of 1.30% (0,49%) for the placebo group.

Correspondents (>5% and >10% weight loss)

Collectively ITT-LOCF 17 of 30 subjects (57%) in the ZON group and 3 out of 30 subjects (10%) in the group VBOs reached weight loss ≥5% weight loss at week 16 (Fisher exact test; p<0,0003); 7/30 subjects ZON and 0/30 VBOs subjects reached ≥10% weight loss at week 16 (p<0,0053).

Other performance measurement

Waist circumference decreased more in group zonisamide during these 16 weeks (103,5 [1,6] cm to 97,2 [1,8] cm vs. from 103.2 [1,9] cm to 100,5 [2,0] cm; time x treatment: F1,49=7,75; p<0,0008). Heart rate decrease is ilaci on average approximately 2 strokes per minute in the full sample (p< 0,0007), although there was no difference between groups. The readings of systolic and diastolic blood pressure did not change in four months.

Safe measurement

Subjects assigned to ZON, reported an average of 2,1 adverse effects (AEs) during the study period, compared with 1.6 AEs for VBOs (t=-1,56; p<0,125). Of individual AEs 10 subjects in the ZON group and 1 in the group RVO reported fatigue (Fisher exact test; p<0,006); there was no other AEs reported good treatment groups. Creatininemia serum was increased from 0.79 (0.03 in) mg/DL at the beginning and 0.92 (0.03 in) mg/DL in the treatment zonisamide, while the change for RVO was 0,76 (0,02) mg/DL to 0.79 (0,02) mg/DL (F1,49=14,82; p<0,0003).

The results of the extension phase

Of the 37 subjects (ZON 20, VBOs 17), which entered a phase of expansion, 36 completed the week 32. One subject in the ZON group withdrew prematurely, citing time constraints. Ten of the 19 subjects group zonisamide and none of the placebo group lost ≥10% of weight at week 32 (p<0,0004). Subjects from group zonisamide had an average weight loss 9,37% (1,64%) at week 32 compared to 1.82% (0,73%) for the subjects of the placebo group (F1,34=13,02; p<0,0001). In terms of absolute weight in kilograms, the change during the 32 weeks for a group of ZON was from 96,88 (3,01) kg to 87,64 (2,95) kg against changes in the group p is acebo with 96,39 (2,95) kg to 94,85 (3,38) kg (time x treatment: F 1,34=of 14.76; p<0,0001).

Waist circumference decreased more in group zonisamide during these 32 weeks (103,5 [2,0] cm to 93.6 [2,2] cm vs. with 103,8 [2,4] 100,5 cm to [2,5] cm; time x treatment: F1,34=scored 8.38; p<0,0001). Both treatments led to a decrease in systolic blood pressure; however, this decrease was greater in the group ZON (129, 1 [2,5] mm Hg to 122,3 [1,8] mm Hg vs with 128,2 [1,8] mm Hg up to 126.8 [1,8] mm Hg; time x treatment: F1,34=2,72; p<0,0047). Diastolic blood pressure decreased in the treatment ZON, but not when VBOs (82,5 [1,8] mm Hg to 79,7 [1,2] mm Hg vs with 82,5 [1,8] mm Hg to 82.2 [1,1] mm Hg; time x treatment: F1,34=1,99; p<0,0403). Heart rate showed no significant change with any treatment.

Bone mineral density in the lumbar spine (L-BMD) did not change over time in any group. Full bone mineral density showed a small, but statistically significant (p<0,017) increased in both groups, although not clinically significant; there was no difference between groups in this respect.

The following measurements on the scale of the impact of weight on quality of life (WKG) (IWQOL) improved more significantly in the group zonisamide compared with the placebo group at week 32: health (p<0,0030), work (p<0,0051), mobility (p<0,0019), activities of daily living (p < 0,0005).

Creatininemia serum increased from 0.7 (0.03 in) mg/DL at the beginning and 0.92 (0.03 in) mg/DL in the treatment zonisamide, while the change for RVO was 0.75 (0,02) mg/DL to 0,77 (0,02) mg/DL (F1,34=br11.01; p<0,0001). There have been no clinically significant changes in the mean values of lipid with any treatment, although some subjects showed a significant decrease.

Conclusion

This randomized study demonstrated that zonisamide showed a strong effect of weight loss when used in addition to the standard, but restrained diet and intervention in lifestyle. Superior effect of the drug over placebo was demonstrated in various tests conducted for both the acute phase (the first 16 weeks)and phase extension. The difference in the effectiveness of weight loss between the active treatment and placebo was evident by 4 weeks, and this gap widened as development studies. Provided discreet incremental diets and intervention in the lifestyle provided for in this study, weight loss of 9.4% for 32 weeks can be regarded as a significant finding.

There was also reduction in some risk factors associated with obesity. Waist circumference decreased more significantly in the treatment zonisamide compared with placebo treatment, which is probably associated with a greater degree of weight loss during active treatment. There was also a significant decrease in systolic d is the pressure of blood although the subjects were not hypertensive at baseline. Improvements were also noted in mobility, General health, professional activity, the actions of everyday life, which is reflected in the overall improvement of quality of life. There have been no significant changes in average levels of lipids, although for some subjects there was a significant reduction.

Zonisamide generally well tolerated. Fatigue was the only adverse effect that occurred with a higher frequency than with placebo treatment. Although in this study they were not observed frequently, these adverse effects often occurred at the test zonisamide in epilepsy: dizziness, impaired cognitive abilities, and drowsiness. Zonisamide is a sulfonamide; there is the potential for hypersensitivity reactions. There were also reports of serious hematologic events. The risk of kidney stones also needs recognition. For the duration of treatment in this study (approximately 8 months), the rate of occurrence of kidney stones in the treatment of zonisamide is estimated as 62,5 per 1000 patient-years of exposure. Consistent with data from trials in epilepsy, an increase creatinine serum was observed in the treatment of zonisamide, but not with placebo. Although the increase (arr siteline an increase of 16%) was significantly no further increase in the phase of expansion was not; no value has exceeded the upper limit of the normal range and there were no clinical events associated with this increase.

EXAMPLE 2

35-year-old obese woman (weight 271 pounds, BMI of 40 kg/m2), which failed to benefit from the numerous interventions weight loss, start with 150 mg/day of bupropion, and the dose was increased after 5 days, 150 mg twice a day. After one month of treatment, she lost 5 pounds, but gained 3.4 lbs during the second month, therefore, the total weight loss was 1.6 pounds after 2 months on bupropion. At this point, the mode was added zonisamide 100 mg/day and the dose was increased after 2 weeks to 200 mg/day. After one month on combination therapy, the patient lost 11 pounds and was not informed about any side effects. No further information is available because the patient moved.

EXAMPLE 3

47-year-old obese woman (weight 246 lbs, BMI 41,4 kg/m2), which has not benefited from the various treatments, beginning with zonisamide 100 mg/day and the dose was gradually increased to 400 mg per day for the following 4 weeks. After one month of treatment, she lost 4.6 pounds, but during the second month there was no further weight loss. At this point, the dose zonisamide was Uwe is icena up to 600 mg / day; the patient reached an additional weight loss of 0.6 pounds in the next month. Thus, after 3 months of treatment zonisamide total weight loss in the treatment zonisamide was 5.2 lbs. Zonisamide continued in the same dose, bupropion SR was started on 100 mg per day. After 10 days, the dose of bupropion was increased to 200 mg per day. A month later, the patient lost 8.2 pounds and was not informed about any side effects. She said that she felt "full" after taking small amounts of food and had more energy. She lost more than 35 pounds for more than ten months on combination therapy without side effects.

EXAMPLE 4

46-year-old obese woman took zonisamide in a clinical trial and achieved weight loss 35.6 per pound for more than 32 weeks. Within 5 weeks, followed by discontinuation of zonisamide, she scored a 7.7 pounds. Zonisamide was started again, but this intervention was unsuccessful in removing the restored weight; after 16 weeks of treatment at doses up to 400 mg/day, the patient gained 1.2 pounds. At this point, was added bupropion at 150 mg/day. After 14 weeks of combined therapy, the patient has lost 9.4 pounds with no adverse effects.

All the above documents are hereby incorporated here in their entirety by reference.

1. A method of treating obesity in a mammal, kiuchumi introduction to him zonisamide and bupropion in effective amounts.

2. The method according to claim 1, in which zonisamide and bupropion are entered separately.

3. The method according to claim 1, in which zonisamide and bupropion entered at the same time.

4. The way to reduce the risk of hypertension, diabetes or dyslipidemia in a mammal, comprising introducing him zonisamide and bupropion in effective amounts.

5. Composition containing bupropion and zonisamide in quantities sufficient to reduce the weight of the mammal.

6. The composition according to claim 5, in which the bupropion and zonisamide are in the form of a unit dosage.

7. The composition according to claim 5, in which the bupropion and zonisamide are in the form of tablets or capsules.



 

Same patents:

FIELD: medicine.

SUBSTANCE: nutraceutical composition is intended for treatment or prevention of adiposity or the conditions bound to adiposity, such as achrestic diabetes (AD, type II) and a syndrome X which includes effective amounts of epigallocatechine gallate (EGCG) and 4 (4-hydroxyphenyl)-2-butanone (KM). Also the method of treatment or prevention of adiposity or the conditions bound to adiposity, such as achrestic diabetes (AD, type II) both a syndrome X and application of EGCG and KM in manufacture of nutraceutical composition is revealed.

EFFECT: synergistic effect at adiposity treatment or prophylaxes.

9 cl, 4 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: in novel compounds of formula (I) X stands for C, N; R1 stands for H or (lower) alkyl, R2 stands for 9(lower) alkyl, -(CH2)n-R2a; R2a stands for C3-C8cycloalkyl, optionally and independently mono-, di-, tri- or tetrasubstituted with the following groups: OH, (lower)alkyl, (lower)alkoxy, 5- or 6-member single-valent saturated heterocyclic ring, containing from one to two heteroatoms, independently selected from nitrogen, oxygen and sulfur, said heterocyclic ring being optionally and independently mono-, di- or tri-substituted with the following groups: OH, (lower)alkyl, (lower)alkoxy, 5- or 6-member single-valent heteroaromatic ring, containing from one to two heteroatoms, independently selected from nitrogen, oxygen and sulfur, said heteroaromatic ring being optionally and independently mono-, di- or tri-substituted with the following groups: OH, (lower) alkyl, (lower)alkoxy, C3-C6cycloalkyl; R3 stands for C3-C6cycloalkyl, being optionally and independently mono-, di- or tri- or tetra-substituted with groups: OH, (lower) alkyl, (lower)alkoxy, phenyl, which optionally and independently is mono-, di- or tri- or tetra-substituted with groups: OH, (lower)alkyl, (lower)alkoxy, halogen, (lower)alkylamino, halogenated (lower)alkyl, halogenated (lower)alkoxy, nitro; R4 stands for 5- or 6-member single-valent heteroaromatic ring, containing from one to two nitrogen heteroatoms, said heteroaromatic ring being optionally and independently mono-, di- or tri- substituted with the following groups: OH, (lower) alkyl, (lower)alkoxy, halogen; naphtyl, which optionally and independently is mono-, di- or tri- substituted with groups: OH, (lower)alkyl, (lower)alkoxy, halogen, (lower)alkylamino, halogenated (lower)alkyl, halogenated (lower)alkoxy, nitro; or phenyl, which optionally and independently is mono-, di- or tri- substituted with groups: OH, (lower)alkyl, (lower)alkoxy, halogen, nitro, halogenated (lower)alkyl, halogenated (lower)alkoxy, cyano, (lower)alkylsulfonyl, -NR7R8; or two neighbouring substituents in said phenyl residue together represent -O-(CH2)p-O-, -(CH2)2-C(O)NH-; R5 and R6 each independently represent H, (lower)alkyl; R7 and R8 each independently represent hydrogen, (lower)alkyl, or R7 and R8 together with nitrogen atom, to which they are bound, form 5- or 6- member saturated or aromatic heterocyclic ring, which optionally contain nitrogen as additional heteroatom; said saturated or aromatic heterocyclic ring, being optionally substituted with the following groups: OH, (lower)alkyl, (lower)alkoxy; m equals 1 or 2, n equals 0 or 1, p equals 1, 2 or 3; or their pharmaceutically acceptable salts.

EFFECT: increased antagonistic activity of compounds.

19 cl

FIELD: chemistry.

SUBSTANCE: invention pertains to new derivatives of 2-pyridinecarboxamide and their pharmaceutical salts, which have glucokinase activating properties. In formula (I): D represents O or S; R2 and R3 each represents a hydrogen atom; formula (II) represents triazole group, imidazole group, thiazole group and pyridine group, which can have in the ring, 1 or 2 substitutes; formula (III) represents a thiazole group, thiadiazole group, isoxazolyl group, pyrazine group, pyridothiazolyl group or pyridyl group, ring B can have 1 or 2 substitutes. The invention also relates to pharmaceutical compositions based on the invented compounds.

EFFECT: new derivatives can be used for treating such diseases as sugar diabetes.

19 cl, 5 tbl, 165 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to new compounds with general formula (I) , where: R and Ri stand for phenyl, which can be substituted with 1, 2, 3 or 4 substitutes, which can be identical or different and chosen from a group consisting of chlorine, iodine, bromine, fluorine, trifluoromethyl and cyano. R2 and R3 can be identical or different and represent C1-5 branched or straight alkyl group. The alkyl group can be substituted with 1-3 fluorine atoms, or R2 and R3 - together with a nitrogen atom, with which they are bonded to, form pyrrolidine or piperidine ring. R7 represents hydrogen, C3-8 cycloalkyl, pyrrolidinyl or piperidinyl. The invention also pertains to salts of these derivatives used in pharmacology, as well as to compounds with general formula (IV), their pharmaceutical compositions, and their use.

EFFECT: obtaining new biologically active compounds which can function as modulators of cannabinoid receptors.

9 cl, 3 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: application of asimadolin or its pharmaceutically acceptable sals is proposed for preparation of pharmaceuticals for indigestion treatment: gastroparesis, gastroatonia, gastroparalysis and the digestive tract stenosis in particular. Medication is effective for tonus modulating of the digestive tract, satiation. Registered, that asimadolin (N-methyl-N-[(1S)-1-phenil-2-((3S)-3-hydroxipyrrolidin-1-il)ethyl]-2,2-dyphenylacetylene (EMD 61753), a selective modulator of the opiate kappa-receptors) depending on the dose, contributes to consumed food volume increase without afterdinner symptoms: bloat, nausea, pain after meal.

EFFECT: creation for effective medication for tonus modulating of digestive tract, satiation.

8 cl, 5 dwg, 4 tbl

FIELD: medicine, pharmacology.

SUBSTANCE: composition for treatment of obesity and associated metabolic syndrome is proposed. The composition contains extract of green tea, extract of Coleus forskholii, extract of Yerba Mate, extract of Betula alba, with definite content of biologically active substances taken in definite amount. Also described is composition for treatment of obesity and associated metabolic syndrome including extract of green tea, extract of Coleus forskholii, extract of guarana, extract of Betula alba, with definite content of biologically active substances taken in definite amount.

EFFECT: compositions are efficient for treatment of obesity and associated metabolic syndrome.

16 cl, 9 dwg, 4 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the bonds of the formula (I) and their pharmaceutically acceptable salts in the capacity of modulators of receptors CB1 and to the pharmacological composition on their basis. Bonds can be used for treatment and prophylaxis of diseases, which are associated with the modulation of receptor CB1, for example, obesity and diabetes of type II. In the general formula (I) R1 means hydrogen or the lowest alkyl; R2 means hydrogen, the lowest alkyl, the lowest alkenyl, the lowest alkoxy-lowest alkyl, the lowest alkoxycarbonilamino-group or - (CH2)m-R2a; or R1 and R2 form together with atom of nitrogen to which they are attached, a 5-or 6-member saturated heterocyclic ring; R2a means cycloalkyl, which is not necessarily mono- or tetra-substituted independently by hydroxy-group, the lowest alkyl; C3-6cycloalkenyl, 5- or 6-member monovalent saturated heterocyclic ring, which contains from one to two heteroatoms, independently selected from nitrogen and oxygen; 5- or 6-member monovalent heteroaromatic ring, which contains from one to two heteroatoms, independently selected from nitrogen and oxygen, here note that the said heteroaromatic ring is not necessarily mono-substituted independently with the lowest alkyl; or phenyl which is not necessarily mono- or di-substituted independently with the lowest of the alkoxy group, halogen, halogenated lowest alkyl, halogenated lowest alkoxy group or nitro-group; R3 means the lowest alkyl, the lowest alkoxy-lowest alkyl, diphenyl-lowest alkyl or - (CH2)n-R3a; R3a means C3-6cycloalkyl which can be not necessarily condensed with the phenol ring; or C3-6cycloalkyl, which can be not necessarily mono-, di- or trisubstituted independently hydroxy-group, the lowest alkyl, C3-6cycloalkenyl, 5- or 6-member monovalent saturated heterocyclic ring, which contains from one to two heteroatoms, independently selected from nitrogen and oxygen, here note that the said heterocyclic rings are not necessarily mono-substituted independently by the lowest alkyl, 5- or 6-member monovalent heteroaromatic ring containing one heteroatom, independently selected from oxygen and sulfur, the aforesaid heteroaromatic ring being not necessarily mono-substituted independently with the lowest alkyl, or the phenyl, which can be not necessarily mono-, di- or trisubstituted independently by the hydroxy-group, lowest alkyl, lowest alkoxy-group, halogen, halogenated lowest alkyl, halogenated lowest alkoxy-group or nitro-group; R4 means the lowest alkyl the lowest alkoxycarbonyl; C3-6 cycloalkyl, 5- or 6-member monovalent heteroaromatic ring, which contains one or two heteroatoms, independently selected from nitrogen, the said heteroaromatic ring being not necessarily mono-substituted independently with the lowest alkyl, lowest alkoxy-group; phenoxy-lowest alkyl, in which the phenyl part is not necessarily mono-, di- or trisubstituted independently by the lowest alkoxy-group; or the phenyl, which not necessarily can be mono-, di- or trisubstituted independently, by the lowest alkyl, by the lowest alkoxy-group, by halogen, halogenated lowest alkyl, halogenated lowest alkoxy-group or nitro-group; or two adjusted substitutes of the said phenyl remainder indicate together -O-(CH2)p-O- or -(CH2)2-O-; R5 and R6 each indicates a substitute independently selected from hydrogen of lowest alkyl; R7 indicates hydrogen; m indicates 0,1 or 2; n indicates 1.

EFFECT: new bonds possess useful biological properties.

28 cl, 4 dwg, 380 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to the obtaining of the new derivatives of benzamide of the formulas (I), which possess the activating influence on glucokinase, which can be used for treating of diabetes and obesity: where X1 and X2 represent oxygen, R1 represents alkylsufonyl, alkaneyl, halogen or hydroxyl; R2 represents alkyl or alkenyl, R3 represents alkyl or hydroxyalkyl, ring A represents phenyl or pyridyl, the ring B represents thiazolyl, thiadiazolil, isoxazoleyl, pyridothiazolyl or pyrazolyl, in which the atom of carbon of ring B, which is connected with the atom of nitrogen of the amide group of the formula(I), forms C=N bond with ring B.

EFFECT: obtaining new bioactive benzamides.

12 cl, 166 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds with the general formula (I) in the racemic, enantiomeric form or in any combination of these forms and in which: A represents -CH2-, -C(O)-, -C(O)-C(Ra)(Rb)-; X represents -CH-; Ra and Rb independently represent the hydrogen atom or a radical (C1-C6)alkyl; Rj represents the atom of hydrogen; a radical (C1-C8)alkyl, not necessarily substituted hydroxyl or by one or more identical or different radicals of halogens; (C2-C6)alkenyl; or a radical of the formula -(CH2)n-X1; R2 represents a radical (C1-C8)alkyl not necessarily substituted hydroxyl or by one or more identical or different radicals of halogens; (C2-C6)alkenyl; or a radical of the formula -(CH2)n-X1; each X1 independently represents (C1-C6)alkoxy, (C3-C7)cycloalkyl or heteroaryl, and radicals (C3-C7)cycloalkyl, aryl and heteroaryl are not necessarily replaced by one or more either identical or various assistants chosen from: -(CH2)n'-V1-Y1, halogen and; V1 represents -O-, -S- or a covalent bond; Y1 represents a radical (C1-C6)alkyl, not necessarily substituted hydroxyl or by one or more identical or different radicals of halogens; n represents an integer from 0 up to 6 and n ' - an integer from 0 up to 2 that if n is equal 0 then X1 does not represent a radical alkoxy); or R1 and R2 form together with the atom of nitrogen to which they are attached, heterobicycloalkyl or heterocycloalkyl, are not necessarily replaced by one or more either identical or various substitutes chosen from: hydroxy, (C1-C6)alkyl, not necessarily substituted by hydroxy, (C1-C6)alkoxycarbonyl, heterocycloalkyl and-C(O)NV1'Y1', in which V1' and Y1' independently represent the atom of hydrogen or (C1-C6)alkyl; or R1 and R2 together form a radical of the formula: R3 represents-Z3, -C(RZ3)(R'Z3)-Z3, -C(RZ3)(R'Z3)-(CH2)p-Z3 or -C(O)Z'3; RZ3 and R'Z3 independently represent atom of hydrogen or a radical (C1-C6)alkyl; Z3 represents Z3b, Z3c, Z3d or Z3e; Z3b represents (C1-C6)alkoxy, (C1-C6)alkythio, (C1-C6)alkylamino, or a radical di((C1-C6)alkyl) amino; Z3c represents aryl or a radical heteroaryl; Z3d represents C1-C6)alkoxycarbonyl, aminocarbonyl, (C1-C6)alkylaminocarbonyl, di((C1-C6)alkyl) aminocarbonyl, (C1-C6)alkyl-C(O)NH-, (C3-C7) cycloalkyl, heterocycloalkyl; and radicals (C3-C7) cycloalkyl and heterocycloalkyl are not necessarily replaced by one or more either identical or various substitutes chosen from: (C1-C6)alkoxy, (C1-C6)alkylcarbonyl, (C1-C6)alkoxycarbonyl and oxy, radicals aryl and heteroaryl are not necessarily replaced by one or more either identical or various substitutes chosen from: halogen, cyanogen, nitro, azide, oxy, (C1-C6)alkylcarbonyl-(C1-C6)alkenyl, (C1-C6)alkylaminocarbonyl-(C1-C6)alkenyl, -SO2-NR31R32, heterocycloalkyl, heteroaryl or -(CH2)P'-V3-Y3; R31 and R32 form together with atom of nitrogen to which they are attached, heterocycloalkyl, V3 represents -O-, -S-, -C(O)-, -C(O)-O-, -O-C(O)-, -SO2-, -SO2NH-, -NR'3-SO2-, -NR'3-, -NR'3-C(O)-, -C(O)-NR'3-, -NH-C(O)-NR'3- or covalent bonds; Y3 represents the atom of hydrogen; radical (C1-C6)alkyl, not necessarily replaced by one or more either identical or different radicals of halogens; radical aryl or a radical aryl-(C1-C6)alkyl; Z3e represents a radical of the formula

, Z'3 represents a radical aryl, not necessarily replaced by one or more oreither identical or various substitutes chosen from: halogen, nitro and -(CH2)P"-V'3-Y'3; V'3 represents -O-, -C(O)-, -C(O)-O, -C(O)-NR'3-,-NH-C(O)-NR'3- or covalent bonds; Y'3 represents the atom of hydrogen or a radical (C1-C6)alkyl, not necessarily replaced by one or more either identical or different radicals of halogens; R'3 represents the atom of hydrogen (C1-C6)alkyl or a radical (C1-C6)alkoxy; p represents an integer from 1 up to 4; p' and p" independently represent an integer from 0 up to 4; R4 represents a radical of the formula -(CH2)S-R'4; R'4 represents a radical guanidine; heterocycloalkyl containing, at least, one atom of nitrogen and not necessarily substituted (C1-C6)alkyl or aralkyl; heteroaryl containing, at least, one atom of nitrogen and not necessarily substituted (C1-C6)alkyl or a radical of the formula -NW4W'4; W4 represents an atom of hydrogen or (C1-C8) alkyl; W'4 represents a radical of the formula -(CH2)S-Z4; Z4 represents an atom of hydrogen (C1-C8) alkyl, (C3-C7)cycloalkyl, heteroaryl and aryl; s and s' independently represent an integer from 0 up to 6; and i) if R3 represents -C(O)-Z'3 and R4 represents a radical of the formula -(CH2)S-NW4W'4, and W4 and W'4 independently represent an atom of hydrogen or a radical C1-C6)alkyl, then -(CH2)s represents neither radical ethylene nor radical -(CH2)-CH((C1-C4)alkyl) and ii), if R3 represents -Z3c and Z3c represents phenyl or naphthyl, then phenyl and naphthyl are not substituted by cyanogen; also note that if R3 represents -Z3d, then Z3d, represents only one (C3-C7)cycloalkyl or heterocycloalkyl; or to their pharmaceutically acceptable salts. The invention also relates to the method of obtaining the compounds of the formula (I), to a pharmaceutical composition, and to the application of compounds of the formula (I) and (I ').

EFFECT: obtaining new biologically active compounds on their basis, possessing activity with respect to receptors MC4.

41 cl, 535 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new bonds in the formula (I-0): or its pharmaceutically acceptable salts, where X represents a carbon atom or nitrogen atom; X1, X2, X3 and X4, each independently, represents a carbon atom or a nitrogen atom; ring A of the formula (II): represents tiazolil, imidazolil, izotiazolil, tiadiazolil, triazolil, oxazolil, oxadiazolil, izoxazolil, pirazinil, piridil, piridazinil, pirazolil or pirimidinil; R¹ represents aryl or represents a 4-10- membered monocyclic or bicyclic heteroring, which has in the ring from 1 to 4 heteroatoms, selected from the group, consisting of a nitrogen atom, sulphur atom and an oxygen atom, and R¹ can be independently substituted with 1-3 R4, and, when the specified heteroring is an aliphatic heteroring, then it can have 1 or 2 double bonds; R² independently represents hydroxy, formyl, -CH3-aFa, -OCH3-aFa, amino, CN, halogen, C1-6 alkyl or -(CH2)1-4OH; R3 represents -C1-6 alkyl, -(CH2)1-6-OH, -C(O)-OC1-6 alkyl, -C(O)-OC1-6 alkyl, -(CH2)1-6-NH2, cyano, -C(O)-C1-6 alkyl, halogen, -C2-6 alkenyl, -OC1-6 alkyl, -COOH, -OH or oxo; R4 independently represents -C1-6 alkyl, and the alkyl can be substituted with identical or different 1-3 hydroxyls, halogens, -OC(O)-C1-6 alkyls, and the alkyl can be substituted with 1-3 halogens or -OC1-6 alkyls, -C3-7 cycloalkyl, -C2-6 alkenyl, -C(O)-N(R51)R52, -S(O)2-N(R51)R52,-O-C1-6 alkyl, and C1-6 alkylcan be substituted with a halogen or N(R51)R52, -S(O)0-2-C1-6 alkyl, -C(O)-C1-6 alkyl, and C1-6 alkyl can be substituted with a halogen, amino, CN, hydroxy, -O-C1-6 alkyl, -CH3-aFa, -OC(O)-C1-6 alkyl, -N(C1-6 alkyl)C(O)O-C1-6 alkyl, -NH-C(O)O-C1-6 alkyl, phenyl, -N(R51)R52, -NH-C(O)-C1-6 alkyl, -N(C1-6 alkyl)-C(O)-C1-6 alkyl or -NH-S(O)0-2-C1-6 alkyl, -C(S)-C3-7 cycloalkyl, -C(S)- C1-6 alkyl, -C(O)-O- C1-6 alkyl, -(CH2)0-4-N(R53)-C(O)-R54, -N(R53)-C(O)-O-R54,-C(O)-aryl, it is optional to substitute the halogen, -C(O)-aromatic heteroring, -C(O)-aliphatic heteroring, heteroring, and the heteroring can be substituted with C1-6 alkyl, optionally substituting the halogen or -O-C1-6 alkyl, phenyl, optionally substituting the halogen, -C1-6 alkyl, -O-C1-6 alkyl, halogen, CN, formyl, COOH, amino, oxo, hydroxy, hydroxyamidine or nitro; R51 and R52, each independently, represents a hydrogen atom, C1-6 alkyl or a nitrogen atom, R51 and R52 together form 4-7-member heteroring; R53 represents a hydrogen atom or C1-6 alkyl, R54 represents -C1-6 alkyl or alkyls for R53 and R54 and -N-C(O)- together form 4-7-member hydrogen containing heteroring, or alkyls for R53 and R54 and -N-C(O)-O- together form 4-7-member hydrogen containing aliphatic heteroring and an aliphatic heteroring can be substituted with oxo, or an aliphatic heteroring can have 1 or 2 double bonds in the ring; X5 represents -O-, -S-, -S(O)-, -S(O)2-, a single bond or -O-C1-6 alkyl; a independently denotes a whole number 1, 2 or 3; q denotes a whole number from 0 till 2; m denotes a whole number from 0 till 2, except in the case when one of the X5 represents -O-, -S-, -S(O)- or -S(O)2-, and the other from X5 represents a single bond, and R1 represents aryl, optionally substituted with 1-3 R4, or a hydrogen containing aromatic heteroring, consisting of from 1 to 4 heteroatoms, selected from the group, comprising of a hydrogen atom, sulphur atom and an oxygen atom, in the case, when X5, both represent single bonds or in cases, when R1, both represent aliphatic heteroring. The invention also relates to the bonding in the formula (I-12), and also to the bonding in the formula (I-0), to the pharmaceutical composition, to the glucokinase activator and to the medication.

EFFECT: getting new bioactive compounds which can be used for treatment and/or prophylaxis of diabetes or obesity.

23 cl, 603 ex

FIELD: chemistry.

SUBSTANCE: compounds of formula (I) can be efficient with respect to diseases, in which phosphorylation of Tau protein takes place. , R3 stands for CONR1R2, where R1 and R2 can be substituted with heterocycle; R5, R6, R7 independently on each other are selected from halogen and phenyl; R1, R2 independently on each other stand for hydrogen, (C1-C6)alkyl or together with nitrogen of group CONR1R can form heterocycle.

EFFECT: obtaining novel biologically active compounds.

4 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: derivatives of 1-sulphonyl-4-aminoalcoxyindole of formula (I) are described, or pharmaceutically acceptable salts thereof, where n is 2 or 3; each of R1 and R2 independently of each other stands for hydrogen, or lower alkyl, or R1 and R2 together with corresponding nitrogen atom may be a part of heterocyclic group, which is selected from morpholino, pyrrolidinyl; R3 stands for hydrogen, or R3 and R1 together with R3 nitrogen atom may be a part of four- or five-membered ring, where R1 and R3 together form an alkylene group; R4 stands for hydrogen; R5 stands for hydrogen; R6 stands for naphthyl, phenyl, not necessarily substituted with one or two substituents, each of which may be a lower alkyl, haloid, lower alcoxy, cyano group, lower alkylsulphonyl, acyl, trifluoromethyl, acetamide, or quinolinyle, thienyl, not necessarily halogen-substituted. The said compounds are selective 5-НТ6 antagonists.

EFFECT: pharmaceutical composition is a receptor modulator.

17 cl, 1 tbl, 6 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention describes a combination used in therapeutic, prophylactic or palliative treatment of pain. Proposed combination consists of the following components: (a) alpha-2-delta ligand chosen from habapentine, prehabaline, [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(1-aminomethylcyclohezylmethyl)-4H-[1.2.4]oxadiazol-5-one, C-[1-(1H-tetrazol-5-ylmethyl)cycloheptyl]methylamine, (3S,4S)-(1-aminomethyl-3,4-dimethylcyclopentyl)acetic acid, (1α,3α,5α)-(3-aminomethylbicyclo[3.2.0]hept-3-yl)acetic acid, (3S,5R)-3-aminomethyl-5-methyloctanoic acid, (3S,5R)-3-methylheptanoic acid, (3S,5R)-3-amino-5-methylnonanoic acid and (3S,5R)-3-amino-5-methyloctanoic acid, or pharmaceutically acceptable salts of any of them, and (b) S,S-reboxetine or its pharmaceutically acceptable salt wherein alpha-2-delta ligand and S,S-reboxetine are taken in the range of ratio from 1:10 to 10:1 of mass parts. Proposed combination provides decreasing the dose of each substance that results to declining adverse effects and enhancing clinical utility of compounds. Also, invention describes using this combination and a set comprising this combination.

EFFECT: improved, enhanced and valuable properties of combinations.

8 cl, 3 ex

FIELD: medicine.

SUBSTANCE: method involves carrying out histological study of smear imprint, bioptate or operation preparation. Histological picture corresponding to the first stage of wound process, conservative therapy course is to be complemented with peroral introduction of Pinaverium bromide at a dose of 50 mg thrice a day 10 days long and local transanal instillations 2 ml 0.1% glycerol trinitrate solution twice a day 6 weeks long. Conservative therapy course at the second stage of wound process is to be complemented with Mebeverine hydrochloride at a peroral dose of 200 mg thrice a day 2 weeks long and intramuscular introduction of Dalargin at a dose of 1 mg twice a day 2 weeks long. Conservative therapy course at the third stage of wound process is to be complemented with Mebeverine hydrochloride at a peroral dose of 200 mg twice a day 2 weeks long and intramuscular introduction of Dalargin at a dose of 2 mg twice a day 2 weeks long and local transanal instillations with 2 ml 0.1% glycerol trinitrate solution twice a day 4 weeks long. Conservative therapy course at the second and the third stage of wound process is also to be complemented with peroral introduction of nonsteroid anti-inflammatory means.

EFFECT: enhanced effectiveness of treatment when applied as rational drug the in postoperative period; accelerated rehabilitation; reduced frequency of disease recurrence.

FIELD: organic chemistry, chemical technology, biochemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): wherein both X1 and X2 represent methylene; R3 represents -CR5=CHR6, and R5 and R6 in common with atoms to which R5 and R6 are bound form (C6-C12)-aryl wherein R3 is substituted optionally with 1-5 radicals of the formula: -X4OR9 wherein X4 represents a bond; R9 represents halogen-substituted (C1-C3)-alkyl, and R4 represents -C(O)X5R11 wherein X5 represents a bond, and R11 represents hetero-(C6-C6)-cycloalkyl-(C0-3)-alkyl; X3 represents group of formulae (a) , (b) or (c) wherein n = 0, 1 or 2; R20 represents hydrogen atom (H); R21 is chosen from group consisting of H, -C(O)R26, -S(O)2R26 wherein R23 is chosen from H and (C6-C12)-aryl-(C0-C6)-alkyl; R25 is chosen from H, (C6-C12)-aryl-(C0-C6)-alkyl or -X4S(O)2R26 wherein X4 has above given values; R26 is chosen from group consisting of H, (C6-C12)-aryl-(C0-C6)-alkyl; wherein X3 comprises optionally, except for, one substitute that being in alicyclic or in aromatic ring system represents a radical chosen independently from group consisting of -X6OR17 wherein R17 represents H, (C1-C6)-alkyl, and X represents a bond or (C1-C6)-alkylene; and its N-oxide derivatives, protected derivatives, individual isomers and mixtures of these isomers; and pharmaceutically acceptable salts and solvated of such compounds, its N- oxide derivatives, protected derivatives, individual isomers and mixtures of these isomers. Also, invention describes a pharmaceutical composition possessing inhibitory activity with respect to cathepsin S-proteases based on compounds of the formula (I), and compound of the formula (Ix) given in the invention description. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: improved preparing method, valuable medicinal and biological properties of compounds and pharmaceutical composition.

16 cl, 3 tbl, 17 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to 2-hetaryl-substituted derivatives of 1,2-tropolones of the general formula (Ia): wherein R1 and R2 mean (C1-C6)-alkyl; R3 means hydrogen atom, (C1-C6)-alkyl, nitro-group; Het means six-membered nitrogen heterocycle condensed with one or two benzyl rings that can be substituted with substitutes chosen from group comprising halogen atom, nitro-group, (C1-C6)-alkyl, oxy-(C1-C6)-alkyl, secondary amino-group chosen from anilino-, substituted anilino-, hydroxyethylamino-group, or tertiary amino-group chosen from morpholino-, piperidino-, piperazino-group, 1H-1-imidazolyl. Also, invention relates to a method for synthesis of 2-hetaryl-substituted derivatives of 1,3-tropolone. Method involves condensation of benzoquinones-1,2 with 2-methylheterocycles at heating in the presence of acetic acid taken in the amount providing its role as both a catalyst and a solvent. Also, invention relates to a pharmaceutical composition with antibacterial effect based on 2-hetaryl-substituted derivatives of 1,3-tropolone.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

9 cl, 5 tbl, 3 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition that comprises N-(chloro-4-morpholin-4-yl)-phenyl-N'-hydroxyimidoformamide and β-cyclodextrin sulfobutyl ester or its salt. Invention provides stability of a drug in storage, heating and light effect and shows practice in using also.

EFFECT: improved and valuable properties of pharmaceutical composition.

3 cl, 3 tbl, 7 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel soluble pharmaceutical salts formed from salt-forming active compound of the general formula (I) or (II) and sugar substitute that can be used in preparing medicinal agents useful in pain and enuresis treatment. Salt-forming active substance represents a salt-forming compound among 1-phenyl-3-dimethylaminopropane compounds of the general formula (I) wherein X means -OH, F, Cl, H or group -OCOR6; R1 represents (C1-C4)-alkyl group; R2 represents H or (C1-C4)-alkyl group; R3 represents H or (C1-C4)-alkyl group with a direct chain, or R2 and R3 form in common (C4-C7)-cycloalkyl group and if R5 means H then R4 represents group O-Z in meta-position wherein Z means H,(C1-C3)-alkyl, -PO-(O-C1-C4-alkyl)2, -CO-(O-C1-C5-alkyl), -CONH-C6H4-(C1-C3-alkyl), -CO-C6H4-R7 wherein R7 represents -OCO-C1-C3-alkyl in ortho-position or group -CH2N(R8)2 in meta- or para-position and wherein R8 means (C1-C4)-alkyl or 4-morpholino-group, either R4 represents S-(C1-C3)-alkyl in meta-position, meta-Cl, meta-F, group -CR9R10R11 in meta-position wherein R9, R10 and R11 mean H or F, group -OH in ortho-position, O-(C2-C3)-alkyl in ortho-position, para-F or group -CR9R10R11 in para-position wherein R9, R10 and R11 mean H or F, or if R5 means Cl, F, group -OH or O-C1-C3-alkyl in para-position then R4 means Cl, F, group -OH or O-(C1-C3)-alkyl in meta-position, or R4 and R5 form in common group 3,4-OCH=CH- or OCH=CHO-; R6 means (C1-C3)-alkyl, or salt-forming active substance represents a salt-forming compound among 6-dimethylaminomethyl-1-phenylcyclohexane compounds of the general formula (II) wherein R1' represents H, -OH, Cl or F; R2' and R3' have similar or different values and represent H, (C1-C4)-alkyl, benzyl, -CF3, -OH, -OCH2-C6H5, O-(C1-C4)-alkyl, Cl or F under condition that at least one among radicals R2' either R3' means H; R4' represents H, -CH3, -PO-(O-C1-C4-alkyl)2, -CO-(O-C1-C5-alkyl, -CO-NH-C6H4-(C1-C3)-alkyl, -CO-C6H4-R5', CO-(C1-C5)-alkyl), -CO-CHR6'-NHR7' or unsubstituted either substituted pyridyl, thienyl, thiazolyl or phenyl group; R5' represents -OC(O)-(C1-C3)-alkyl in ortho-position or -CH2N(R8')2 in meta- or para-position and wherein R8' means (C1-C4)-alkyl, or both radicals R8' in common with nitrogen atom (N) form 4-morpholino-group, and R6' and R7' have similar or different values and represent H or (C1-C6)-alkyl under condition that if both radicals R2' and R3' represent H then R4' doesn't mean -CH3 when R1' represents additionally H, -OH or Cl, either R4' doesn't mean H when R1' represents additionally -OH. Also, invention relates to a medicinal agent based on indicated salts.

EFFECT: valuable medicinal properties of salts and drug.

14 cl, 1 tbl, 8 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new amide-type carboxamide derivatives of formula [1] , wherein X represents -N= or -CH= group; R1 represents halogen atom, lower alkyl and a like; R1 represents -CO-R21-R22 (meanings of R21 and R22 are as defined in claim 1); Y1 and Y2 are independently halogen atom, lower alkyl, lower alcoxy group, and a like; ring A represents phenyl and a like; or pharmaceutically acceptable salts thereof. Said derivatives are useful as FXa inhibitors. Also disclosed are pharmaceutical composition based on abovementioned compounds and uses thereof.

EFFECT: new amide-type carboxamide derivatives.

7 cl, 105 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel aromatic compounds that can be used in treatment of diseases or pathological states accompanying by inflammation, for example, chronic inflammation diseases. Invention describes compound of the formula (II): wherein G means phenyl, pyridinyl, pyrazolyl and wherein G is substituted with one or some groups R1, R2 or R3; Ar means naphthyl; X means (C5-C8)-cycloalkyl or cycloalkenyl optionally substituted with 1-2 oxo-groups, phenyl, furanyl, pyridinyl or pyrazolyl; Y means a bond or saturated either unsaturated branched or unbranched (C1-C4)-carbon chain wherein one or some methylene groups are optionally and independently substituted with oxygen (O) or nitrogen (N) atoms; Y is optionally substituted with oxo-group; Z means phenyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, morpholinyl, thiomorpholinyl, piperidinyl, piperidinonyl, piperazinyl, pentamethylenesulfoxidyl wherein each of them is optionally substituted with 1-3 (C1-C6)-alkyls or group -CONH2, (C1-C6)-alkyl, nitrile, hydroxy-group, (C1-C6)-alkoxy-group, secondary or tertiary amine wherein amine nitrogen is bound covalently with (C1-C3)-alkyl or (C1-C5)-alkoxyalkyl, tetrahydrofuranyl-(C1-C3)-alkyl, nitrile-(C1-C3)-alkyl, carboxamide-(C1-C3)-alkyl; R1 means independently in each case (C1-C10)-alkyl which is optionally partially or completely halogenated and optionally substituted with 1-3 hydroxy-groups, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl wherein each of them is optionally substituted with 1-3 groups -CN, halogen atom, (C3-C6)-alkynyl branched or unbranched carbon chain and one or some methylene groups is optionally replaced for atom O and indicated alkynyl group is optionally substituted with one or some (C1-C4)-alkyl groups; R2 means branched or unbranched (C1-C6)-alkyl that is optionally partially or completely halogenated, branched or unbranched (C1-C4)-alkoxy-group that in each case is optionally partially or completely halogenated, halogen atom, (C1-C6)-alkoxy-group, hydroxy-group, mono- or di-(C1-C4)-alkyl-amino-group, group -OR6, nitro-group or group mono- or di-(C1-C4)-alkyl-amino-S(O)2 that is optionally partially or completely halogenated, or group -H2NSO2; R3 in each case means independently phenyl, pyridinyl, pyrimidyl, pyrrolidinyl, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, (C1-C4)-alkynyl group or branched or unbranched (C1-C6)-alkoxy-group wherein each of them is optionally partially halogenated, -OR18 or (C1-C6)-alkyl optionally substituted with group -OR18, amino-group or mono- either di-(C1-C5)-alkyl-amino-group, (C2-C6)-alkynyl branched or unbranched carbon chain wherein one or some methylene groups are optionally replaced for atom O, and indicated alkynyl group is optionally substituted with one or some (C1-C4)-alkyl groups; R6 means (C1-C4)-alkyl that is optionally partially or completely halogenated; in each case R18 means independently hydrogen atom, (C1-C4)-alkyl; W means atom O, and its pharmaceutically acceptable derivatives. Also, invention describes a pharmaceutical composition containing these compounds and a method for treatment of disease mediated by cytokines and based on indicated compounds. Invention provides synthesis of novel compounds possessing valuable biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of treatment.

12 cl, 1 tbl, 38 ex

FIELD: chemistry.

SUBSTANCE: in general formula (I) , R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 can be similar or different and represent, each independently, hydrogen, halogen, hydroxyl, unsubstituted (C1-C6)alkyl, (C1-C6)alkoxy, or neighbouring groups R2 and R3 together with carbon atoms to which they are bound, can form benzol ring; R13 and R14 can be similar or different and represent each independently, hydrogen, unsubstituted (C1-C6)alkyl, optionally, R13 and R14 together with nitrogen atom can form 5-, 6-member heterocyclic ring, where heterocycle also can be substituted (C1-C6)alkyl, and it can have "additional heteroatoms", selected from O, N; "n" is an integer in interval from 1 to 4, and carbon chain, to which it relates is linear.

EFFECT: compound possess the characteristic of activity modulators 5-HT and can be applied for treatment of such diseases as anxiety, depression, convulsive syndromes, migraine.

15 cl, 67 ex

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