Method of combined treatment and combinations of medications applied in it

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to method of introduction of at least one active medicinal substance to patient, dependent on said active medicinal substance or active substances, method includes stages at which a) at least one, transdermal therapeutic system (TTS), which contains first active medicinal substance, for transdermal introduction of said active substance during given time period is applied and b) at the beginning or during transdermal introduction applied is at least one pastille, which contains the same active substance or second active substance, or additional active substances with the same indications for application as first active substance.

EFFECT: method of combined treatment and applied for it combinations of medications are described.

23 cl, 1 ex

 

The present invention relates to the introduction of active medicinal substances to patients, depending on the introduction of the mentioned active substances, with the goal of medical treatment, in particular long-term treatment. The invention also relates to combinations of medicines applicable in such methods of treatment, and use of active medicinal substances in the above-mentioned treatment methods.

The invention in particular relates to the combined treatment with percutaneous therapeutic systems and the simultaneous introduction of one or more tablets, which releases the active substance(s) through the mucous membrane in the oral cavity.

Proposed in the invention combination therapy may, in particular, successfully applied for the treatment of patients requiring long-term treatment, or in the case of a basic drug therapy for a long time, and when at the beginning or during long-term treatment must be rapid or rapid onset of action of the medicinal product and/or during long-term treatment unexpectedly temporarily increases the need for the active ingredient.

This task is of great importance, in particular in the treatment of acute or chronic pain (e.g., treatment for pain in patients with cancer), when the and to achieve long-lasting relief providing long-term or basic therapy with analgesics (e.g., opiates) and adjust the input dose depending on the intensity of pain felt by the patient. The goal of this therapy is that enough to ease the pain and avoid overdose.

However, when conducting such long-term or basic therapy with the use of an individually adjusted dose of active ingredient may occur a so-called "sporogonia pain". The term "sporogonia pain" means pain that arise from time to time in the course of or in spite of the constant routine analgesics (long-term medication) and are more intense than the pain, to facilitate providing a long-term treatment. Often the reason sporogonic pain can be installed and removed, for example, it can be arbitrary motion, certain provisions in the body, touch, or in the case of prolonged pain in the gastro-intestinal region certain foods. To facilitate data sporogonic pain patient prescribed supplementary analgesics in addition to analgesics taken as part of the basic therapy, which are usually the drugs controlled release of the active substance.

Percutaneous introduction of medicinal substances (acting medicinal substances), in particular, by using the percutaneous therape the political systems (TTS), has a number of generally known advantages, including, for example, controlled and prolonged delivery of the active substance and the exception presystemic metabolism. However, despite these advantages, their common drawback is the fact that the introduction of drugs through the skin is limited both from the point of view of quality and quantity and that the absorption of the active substance through the skin after applying what begins only with a significant delay in time.

Specialists in the art it is known that the skin is not absorbing the environment, and prevents the ingestion of foreign bodies and, therefore, medicinal substances. Because of this property of the skin is referred to delay the start of the action. This phenomenon was introduced the term "lag time". It is implied that he means the time between the first application of percutaneous insertion of a medicinal product, for example, the TTS and the first appearance of measurable concentrations in the plasma or the first appearance of the expected physiological effect of the drug.

This time, in particular, is crucial in cases where the medicinal substance is injected not only in the basic or long-term treatment is, that is, for a long time, but also when it is necessary that the medicinal substance began to act as quickly as possible after its first introduction, for example in the case of the introduction of analgesics direct action. It is known that the first application of what or any sporogonic pain can eliminate or reduce the lag time when using the advanced tools that allow for rapid delivery of the active substance, for example by intravenous injection. However, this combination also has disadvantages, since intravenous injection should always be done by a doctor. The pill at the same time using what also does not help, because the absorption of opiates gastrointestinal tract also happens only with some delay.

In addition, in the case of reception of tablets after the passage of the active substance through the gastro-intestinal tract it reaches the liver, where metabolism, resulting in it losing its effect. This phenomenon is known experts in the art as the so-called "presystemic metabolism". In particular, in the case of reception of opiates, in which the aromatic ring marvinney frame structure contains a free hydroxyl group (for example, morphine and hydromorphone), early starts phase II khimicheskogo the transformation, i.e. glucuronidation (conjugation with glucuronic acid).

Taking into account the above disadvantage (delayed onset of action) percutaneous introduction not applicable in the case of sudden-onset pain, for example sporogonic pain. At the initial stage of development of therapy of cutaneous or percutaneous injection at the same time attempts were made to find ways to reduce the lag time and to accelerate the onset of action.

One possibility to speed up the percutaneous absorption of the active substance is that what is placed on the skin is subjected to ultrasonic processing or processing by the method of heat dissipation. The disadvantage of these methods is the complexity of their implementation, and therefore they did not receive the distribution.

Other ways to increase the absorption rate of drugs when percutaneous introduction based on the removal or partial breach the stratum corneum by means of laser processing or multiple bonding and tearing adhesive strips (so-called "peeling"). Although these two methods also reduce the lag time, their disadvantage is that they contribute to the permeation of not only the desired medicinal substances, but also other unwanted components of the medicinal product and the microorganism is in, such as bacteria or fungal spores. In addition, the disadvantage is that to exfoliate the skin, you must remove what. However, as is well known to physicians, when peeling what it loses its ability to grip, because with what remove the top layer of skin in contact with the sticky substance.

Another way to increase the rate of absorption through the skin is the use of electrical current. As is well known to physicians, the use of this method, known as "iontophoresis", it is not possible without causing pain. This also applies to so-called needle patches; this skin medication is fixed on the body using a hollow needle penetrating the skin. The delivery of the active substance takes place through the hollow needle, which serve as a means of fixation. Obviously, this can not be called skin or percutaneous introduction in the classical sense of the word, and is essentially a subcutaneous injection of a medicinal substance with all known shortcomings (the need for sterile needles, the impossibility of long-term release and so on).

Thus, the present invention is to provide a method for facilitating the introduction of the drug to the patient to conduct basic or long-term treatment, i.e. for a long time is, and reducing or eliminating the above mentioned disadvantages (in particular, the lag time and presystemic metabolism).

In addition, the invention aims, in particular, a method of medical treatment that facilitates the initiation or continuation of basic or long-term care and providing onset of their therapeutic action as soon as possible after the first application. In other words, the lag time should be minimized.

Another objective of the invention is to provide methods of treatment, allowing periodically during long-term treatment to introduce at least one additional dose of medicinal substance with minimal lag time to the patient with increased demand for medicinal substance.

In addition, the task of the invention is to provide means applicable to the implementation of the mentioned methods.

These objectives of the invention is solved by means of the method according to claim 1, as well as products and use the rest of the items.

Thus, the present invention relates to a method of introducing at least one current medicinal substance to the patient, depending on the introduction referred to the active substance or active substances. More precisely, this method is a method of carrying out long-lasting the CSO treatment. Proposed invention is a method of treatment includes a stage on which:

apply at least one transdermal therapeutic system (TTS),

contains the first effective drug for percutaneous introduction of the mentioned active substance within a specified period of time, and

b) using at least one toffee at the beginning or during the

percutaneous introduction, containing the same active substance or the second active substance, or more active substances with the same indications as the first active substance.

Through the use of what on the patient's skin to deliver the dose of the active substance with a slow, controlled release, necessary to start and/or continue long-term treatment, and provide a systemic effect. The duration of percutaneous injection depends mainly on the total quantity of the active substance contained in the relevant acts, the type of the contents of the active substance, surface area of application of the acts and speed of release. Typically, the duration of release from what is from about 6 to 72 hours, in particular from 12 to 24 or 48 hours. After this time, what used to remove and, if necessary, replace new what. Total long the awn long-term treatment may be one or more days or an indefinite period of time, while there are indications.

The toffee mentioned at the stage (b), is a thin and flexible plate dosage form, preferably applied oral and releasing the contained active ingredient(s) in the oral cavity, while the absorption of the active substance occurs mainly through the mucous membrane of the oral cavity (i.e. crosslist). Considering the small thickness of these pastilles (preferably from 0.05 to 1 mm, particularly preferably from 0.1 to 0.5 mm) and short diffusion path release of the active substance begins immediately after getting tablets in the oral cavity. Due to absorption through the mucous membrane in several minutes (about 5-15 minutes) after oral administration of tablets is achieved therapeutically effective levels of the active substance in the plasma. This contributes to the rapid onset of action. Preferably use lozenges, adherent to the mucosa and/or disintegrating in water (body fluids, especially saliva).

According to stage (b) the toffee is used at the beginning or during percutaneous injection. This means that the toffee is used at the beginning of the percutaneous injection (i.e. at the moment when what is placed on the skin) or that the toffee is administered to the patient later, when what had already been posted on to the MS patient and has already begun percutaneous delivery of the active substance.

In the simplest case, the toffee, which is used in the beginning or during percutaneous introduction, contains the same active substance or the same combination of active substances, and that what used for percutaneous introduction. Alternatively or additionally, such a toffee may contain a second active ingredient or additional active substances which/which do not coincide with the (first) active substance contained in the acts, but which/which have the same indications for use, as mentioned, the first active substance. Data active substance may be a drug with the same pharmacological effect; in the case of analgesics that may be, for example, another opiate. If what contains a combination of two or more active substances, toffee, which is at the stage (b) impose, in addition to what may not necessarily contain only one of the active ingredients of this combination of active substances.

Proposed invention the combination of percutaneous introduction with the introduction of one or more tablets allows for long-term treatment with a rapid onset of action and rapid dose adjustment, when during long-term treatment flow stage of the disease, which temporarily increases the demand on istvudom substance, in particular, to facilitate sporogonic pain in the process of long-term pain relief. Thus, proposed in the present invention, the methods preferably applicable to the treatment of patients who require rapid or accelerated onset of their therapeutic action in the early long-term treatment or long-term care, or for the treatment of patients during long-term treatment or basic medical treatment temporarily increases the need for the active ingredient.

Thus, in a preferred embodiment of the invention in the first stage of the method of treatment using the TTS containing a first active substance, and in addition to apply toffee, containing the same active substance or the second active substance, or more active substances with the same indications for use. Preferably what and toffee are applied almost simultaneously, i.e. for less than 15 minutes, preferably less than 5 minutes. For a basic treatment of what used within a specified time.

As described above, the introduction of more lozenges preferably carried out once at the beginning of basic therapy. If necessary, during the subsequent course of long-term treatment may additionally apply what I one or more lozenges.

To continue the basic therapy of the patient over a long period of time in accordance with the requirements at regular intervals (for example, after 6, 12, 24, 48, or 72 hours) may apply additional percutaneous therapeutic system containing the active substance, while previously applied, what used each time removed from the skin. Due to this, you can continue long-term treatment or basic therapy for a long time, preferably for at least 24 hours. Long-term treatment may last for several days, weeks, months, or years, if circumstances require disease.

In an additional preferred embodiment of the invention the method of treatment includes at least one stage in which percutaneous therapeutic system used in conjunction with toffee, as described above. This joint use may preferably be carried out at the beginning of treatment (especially in the beginning of the long-term care or basic therapy). Alternatively, the toffee is used simultaneously with each subsequent application of additional acts.

In another particularly preferred embodiment of the invention provides that during the above mentioned period of percutaneous injection or long-term l is ing, at least once referred to impose additional active ingredient or other active substance in the form of tablets with the same indications for use. The dose of active substance is introduced in the form of lozenges, corresponds to the increased need for the active ingredient, which temporarily occurs in a patient during the mentioned period. In particular, this allows to simplify sporogonia pain or bursts of pain that occur during long-term treatment of pain. As a result of rapid systemic exposure to the active substance, is introduced through the mucous membrane through mints, rapid relief of pain. The use of tablets in accordance with the present invention can be easily managed by the patient. If necessary, for example, in the case of intensive sporogonic pain the patient may simultaneously or at short intervals to take two or more tablets.

The amount of active ingredient ("loading dose")contained in the toffee according to the present invention that is administered, for example, after the start of long-term care or for removal sporogonic pain, preferably of 0.1 to 0.7, particularly preferably 0.2 to 0.5 percutaneous insertion of a daily dose.

Preferably proposed in the present invention the methods used is t for the treatment of patients suffering from one or more of the following diseases, conditions and symptoms: chronic pain, asthma, diabetes, risk of heart attack, withdrawal symptoms when quitting Smoking and Parkinson's disease. In particular, in the preferred embodiment, the method is used to eliminate pain. These pain can be chronic and/or acute pain caused, for example, in patients suffering from cancer.

Specialists in the art known medicinal substance, applicable to the treatment of these diseases, conditions or symptoms. For this purpose, in particular, applicable active substances selected from the group including analgesics, protivobloshinye tools, antidiabetics, vasodilator, anti-withdrawal and anti-Parkinsonian tools.

In General, for the implementation of the present invention can be used with all applicable percutaneous active substances, since in this case also means that the mentioned active ingredients quickly absorbed through the mucous membrane of the oral cavity. If the speed crosslisted absorption of any active ingredients, selected for percutaneous introduction, is the lack of such active ingredient, as described above, may be amenano other active substance with the same indications for use, as input percutaneous active ingredient, but with a better ability to be absorbed through the mucous membrane.

Preferably for percutaneous introduction choose active medicinal substance with a low rate of penetration through the skin to provide the desired delayed and prolonged effect. Alternatively, the rate of release of active substance from percutaneous therapeutic system control method, well-known specialists in the field of technology, if necessary, reduce, for example, by means of auxiliary substances, applicable for these purposes, or by using membranes, inhibiting the release of the acting substance.

In the present invention is applicable primarily active substances, with high efficiency, i.e. active substances, the daily dose which is calculated in milligrams (for example, from 1500 mg) and pharmacologically acceptable salts which dissolve easily in water (preferably more than 10% in terms of mass). This applies in particular to opiates and their salts, and their use is particularly preferred.

In the case of elimination of pain, in particular, analgesics are used preferably from the group of opiates.

Under "analgesics" from the point of view of the present invention refers to pharmaceutical substances, the cat is who in therapeutic doses applicable to weaken or suppress pain. Among them, in particular, are highly effective analgesics direct action, the so-called opiates. This group of active medicinal substances, among others, include morphine, heroin and other derivatives of morphine; derivatives dihydromorphine, such as hydromorphone (Dihydrocodeine), oxycodone; derivatives morphinan, such as Levorphanol, buprenorphine; analgesics from the group of peptides, such as peptides, Ketobemidone, loperamide, Diphenoxylate; methadone and its derivatives, such as levomethadone, dextromoramide, dextropropoxyphene; fentanyl and its derivatives (for example, Alfentanil, Sufentanil, Remifentanil), derivatives of benzomorphan, such as pentazocine and derivatives phenylaminopyrimidine, such as tilidin; tramadol. To resolve sporogonic pain particularly preferred are the opiates with quick and short-term action, such as morphine, tilidin, oxycodone, hydromorphone, buprenorphine, fentanyl and levomethadone.

Preferred for percutaneous introduction analgesics are, with a low rate of penetration through the skin. Their example is buprenorphine.

Besides, it is also applicable analgesics from the group comprising: Metamizole, venison, propifenazona, flupirtine, nefopam; anti-epileptic agents such as carbamazepine, gabapentin, clonazepam; antidepressants such as as the itriptyline.

The invention also relates to the use of combinations of active substances consisting of two or more medicinal substances, in particular combinations of the mentioned analgesics.

Obviously, the practical application of the present invention is of particular importance with the introduction of analgesics, as for a patient experiencing acute pain, it is unacceptable to wait until the beginning of drug action at the end latency. In this case, an acceptable time lag of up to several minutes (5-10 minutes). This requirement respond orally applied according to the invention lozenges for crosslisted the introduction of the active substance.

The present invention also relates to the combination of drugs, including at least one transdermal therapeutic system (TTS) and at least one containing the active substance toffee, with what it contains(-at) the first active drug substance, and toffee(s) contain the same first active substance or the second active substance, or more active substances with the same indications for use as the first active substance.

The term "medicinal product" generally refers to substances or mixtures of substances, applicable in medicine or veterinary medicine, which contain on actuuse medicinal substance(s), and additionally conventional components (inactive excipients), providing pharmacological applicability of the active substance. Proposed invention the combination of drugs includes drugs contained in various pharmaceutical forms, namely, on the one hand, in the form of what, and, on the other hand, in the form of lozenges.

In the proposed invention the combination of drugs a certain number of transdermal therapeutic systems (TTS)containing the same active medicinal substance and also preferably have the same composition, corresponds to a certain number of pastilles. These tablets preferably contain the same active substance, and that what, or different active substance with the same indications for use as the active ingredient contained in what. As for tablets, it is also preferred that all of the tablets included in the mix were mostly of the same composition.

The mentioned correspondence between a certain number of acts and a certain number of pastilles preferably can be provided due to the fact that what and lozenges are placed in a common container in the form of a "kit" or "set".

Proposed invention the combination of drugs contains, at least, one who has what and at least one toffee. The number and what number of pastilles in combination may not necessarily be the same or different. In particular, in the case of applications for pain relief it is preferable that the number of tablets in combination exceeded the number of percutaneous therapeutic systems. Lozenges that are included in some combination of drugs, usually have the same content of active substance. In addition, it may be advantageous to this combination consisted of two or more groups of pastilles that are different from one another dose of the active substance and marked accordingly.

Active substances contained in transdermal therapeutic systems, and lozenges, are included in the combination of drugs, preferably selected from the aforementioned active substances and groups of active substances. Also preferably, percutaneous therapeutic systems included in the combination of medicines, provided the system percutaneous introduction of the contained active substances for at least 24 hours, preferably at least 48 hours. The tablets included in the combination of drugs, preferred are tablets for oral administration, therapeutic action of which shall begin not later than 15 minutes, preferably, ENISA least 5 minutes after oral administration. In addition, it is preferable that tablets had the ability to adhere to the mucosa and/or disintegrate in the aquatic environment.

The invention also includes the use of active medicinal substances, in particular active substances selected from the above-mentioned active substances and groups of active substances for the manufacture of the described combination of the drugs according to the invention, for the treatment of patients, depending on the introduction of such an active substance, for the purpose of conducting long-term care or basic care. These combinations of drugs are preferably used in the described methods of treatment and in the described therapeutic purposes.

What and lozenges according to the present invention can be manufactured by known pharmaceutical methods; the compositions of these drugs and the used excipients well known to specialists in this field of technology.

What applies for the purposes of the present invention, are described, for example, in patents Germany DE 3939376 C1, DE 19923551 A1 and DE 19834005 A1.

What applied in accordance with the invention preferably have a multilayer structure, that is, have two, three or multiple layers. In addition, the multilayer structure of what may, in particular, to include one or more layers, you have the security of:

- bonding with pressure adhesive layers

porous layers and

hydrogel layers.

At least one of the layers contains what is described above, the active substance or combination of active substances. Preferably the TTS according to the present invention have bonding with pressure adhesive layer used to attach what to the skin of the patient and preferably contain the active substance.

Containing the active ingredient layer (or matrix) what preferably consists of bonding with pressure adhesive, water-insoluble polymer such as partially esterified polyacrylate, polyisobutylene (PIB) or silicones, or mixtures of such polymers; additionally, there may be added known excipients (for example, soljubilizatory, emulsifying agents, permeation enhancers, preservatives).

The toffee used in accordance with the invention, without limiting the invention to provide a plate-like product for oral administration of active substances. In this case, the active substance dissolved in the polymer or mixture of polymers or dispersed in the polymeric matrix. The polymers used to manufacture the tablets should preferably be soluble in water to the toffee, as required, quickly, ideally within bore the channels at seconds (for example, most 5-30 seconds) to dissolve in the saliva of the mouth.

Applicable polymers for the manufacture of pastilles are, in particular, polymers from the group comprising glycols, starch and starch derivatives, polyvinyl alcohols and polyacrylic acid (e.g., Carbopol®) or polyvinylpyrrolidone (polyvidone, for example, Kollidon®). In addition, tablets may contain one or more auxiliary substances, such as softeners, emulsifiers, surfactants, soljubilizatory, fillers, agents, causing disintegration, dyes, flavouring flavouring agents and sweeteners, preservatives; such auxiliary substances known to specialists in this field of technology. Lozenges applicable for purposes of the present invention, and corresponding methods for their manufacture are described, for example, in patents Germany DE 10207304 A1 and US 6709671 B2.

Example 1

Hereinafter the invention is described in more detail by the following example.

This example relates to the treatment of a patient suffering from pain. For long-term treatment or basic therapy have produced what (or what)containing buprenorphine, as described in the Federal Republic of Germany patent DE 3939376 C1 (see table below). This what has caused on the skin of a patient suffering from pain, where she remained for a specified period of use (for example, 24, 48, or 72 hours).

Used what contain drug substances and excipients according to the following table:

Drug substance or excipientThe number on what [mg]
Buprenorphine base20
Oleyl the oleate30
Levonova acid20
Based adhesive polyacrylate, crosslinked with aluminum680
Fabric made of polyethylene terephthalate as a sublayer518
A film of polyethylene terephthalate with a thickness of 23 microns80
Film of siliconized polyethylene terephthalate as a protective layer919

The rate of release of such what is 35 µg/h (in terms of release of buprenorphine from the corresponding single what).

The patient was orally introduced toffee. The toffee contained 10 wt.% of buprenorphine hydrochloride in a mixture of polymers containing 65 wt.% Carbopol® 2 wt.% the starch. Single toffee contained 1 mg of buprenorphine hydrochloride, 6,5 mg Carbopol and 2.5 mg of starch.

The high concentration of the drug in the toffee allows the patient to alleviate the pain immediately after the start of long-term treatment because the toffee disintegrates in the oral cavity for about 5-10 seconds, and released buprenorphine (in the form of soluble salts) directly absorbed in the mucous membrane of the oral cavity, resulting in a few minutes reached its therapeutically effective levels in the plasma.

If for percutaneous introduction of the active substances are sporogonia pain to the patient as quickly as possible (i.e. as soon as you begin to feel the first signs of increasing intensity of pain) orally administered one or more tablets containing buprenorphine hydrochloride. Due to the rapid absorption of soluble salts through the mucous membrane of the oral cavity, the patient immediately feels the weakening of acute pain.

Below average levels in plasma, defined as a result of the application containing buprenorphine TTS n=5 healthy volunteers. During the first 12 hours patients suffering from pain, had not received adequate treatment; achieved plasma concentration is less than 30 ng/ml (time of sepastia the Oia). Only after 24 hours was achieved stable level of concentration of buprenorphine in the plasma (about 80-100 ng/ml), corresponding to the basic therapy. This stable level of concentration maintained within about 96 hours after application of the acts.

The invention provides that upon the occurrence sporogonic pains, and also during the first 12 hours after application of the acts impose additional lozenges for oral administration to provide early onset of action of buprenorphine and avoid presystemic metabolism, resulting in quick and effective relief sporogonic pain.

1. The method of introducing at least one current medicinal substance to the patient, depending on the introduction referred to the active substance or active substances, in particular, for long-term care, including a stage on which:
a) apply at least one transdermal therapeutic system containing the first effective drug for percutaneous introduction of the mentioned active substance within a specified period of time, these active substance selected from the group including analgesics, protivobloshinye tools, antidiabetics, vasodilator and ANTIPARKINSONISM funds, and

2. The method according to claim 1, characterized in that during percutaneous introduction additionally use at least one toffee, containing the same active substance or the second active substance, or more active substances with the same indications for use as the first active substance.

3. The method according to claim 1, characterized in that the said patient is a patient:
which at the beginning or during long-term treatment requires rapid or accelerated onset of their therapeutic action, or
which during the mentioned long-term care or basic therapy temporarily increases the need for the active ingredient.

4. The method according to claim 1, characterized in that the first stage used a percutaneous therapeutic system containing a first active substance, and in addition to apply toffee, containing the same active substance or the second active substance, or more active substances with the same indications for use.

5. The method according to claim 1, ex is different, however, that at the expiration of the above period stage percutaneous therapeutic system is repeated at least once to conduct long-term care or basic care of the patient by percutaneous introduction of the mentioned active substance over a long period of time.

6. The method according to claim 5, characterized in that to continue long-term treatment or the standard therapy for a long time, preferably for at least 24 h at regular intervals, preferably at intervals of 6, 12, 24, 48 or 72 hours to enter additional percutaneous therapeutic system containing the aforementioned active substance.

7. The method according to claim 1, characterized in that during the mentioned percutaneous injection or referred to long-term care at least once referred to impose additional active ingredient or other active substance in the form of tablets with the same indications for use, and the dose of the active substance entered using lozenges, corresponds to the increased need for the active ingredient, which temporarily occurs in a patient during the mentioned percutaneous injection or referred to the long-term treatment.

8. The method according to claim 1, characterized in that the quantity of the active substance contained in the toffee, predpochtitelno is 0.1 to 0.7, particularly preferably 0.2 to 0.5 percutaneous insertion of a daily dose.

9. The method according to claim 1, characterized in that the patient is dependent on the introduction of the mentioned active substances and has one or more of the following diseases or symptoms selected from the group comprising chronic pain, asthma, diabetes, risk of heart attack, withdrawal symptoms when quitting Smoking and Parkinson's disease.

10. The method according to claim 1, characterized in that the above occur temporarily increased the need for the active ingredient caused by the increase in the intensity of pain or zaporoghye pain.

11. The method according to claim 1, characterized in that the said active substance or at least one of these active substances are selected from the group including analgesics, protivobloshinye tools, antidiabetics, vasodilator, anti-withdrawal and anti-Parkinsonian tools.

12. The method according to claim 11, characterized in that the said active substance or at least one of these active substances chosen from the group of opiates.

13. The combination of medicines, providing the means of implementation of the method according to claim 1, comprising at least one transdermal therapeutic system (TTS), and at least one containing dei is adequate substance the toffee, these acts contains(-at) the first active drug substance, as mentioned toffee(s) contains the same first active substance or the second active substance, or more active substances with the same indications for use, as mentioned, the first active substance, in fact the first active ingredient selected from the group including analgesics, protivobloshinye tools, antidiabetics, vasodilator and anti-Parkinsonian tools.

14. The combination according to item 13, characterized in that the said second active substance or an additional active substances are selected from the group including analgesics, protivobloshinye tools, antidiabetics, vasodilator and anti-Parkinsonian tools.

15. The combination according to item 13, wherein the transdermal therapeutic system(s) provides a system for percutaneous introduction of the contained active ingredient for at least 24 h, preferably at least 48 hours

16. The combination according to item 13, wherein said toffee(s) applicable for oral administration, and its therapeutic action is commenced not later than 15 minutes, preferably at least 5 min after oral introduction is of lozenges.

17. The combination according to item 13, wherein the toffee(s) dissolves in water environment and/or has the ability to adhere to the mucous membrane.

18. Applying at least one current medicinal substances for the manufacture of a combination of drugs, including:
a) at least one dermal therapeutic system (TTS)containing the first active drug substance from the group including analgesics, protivobloshinye tools, antidiabetics, vasodilator and ANTIPARKINSONISM funds, and
b) at least one toffee, containing the same active substance or the second active substance, or more active substances with the same indications for use, for the treatment of the patient, depending on the introduction of the mentioned active substance, for the purpose of conducting long-term care or standard therapy.

19. Use p, characterized in that the combination is applicable for treatment of the patient:
which at the beginning or during long-term treatment requires rapid or accelerated onset of their therapeutic action, or
which during the mentioned long-term care or basic therapy temporarily increases the need for the active ingredient.

20. Use p, differently the, what long-term care or basic therapy is carried out by applying the mentioned transdermal therapeutic system(s), and the aforementioned temporary increased the need for the active ingredient are provided by the introduction of lozenges.

21. Use p, characterized in that one or more of these pastilles injected at the beginning or continuation of long-term care, which provide a rapid or rapid onset of action.

22. Use p, characterized in that the patient is dependent on the introduction of the mentioned active substances and has one or more of the following diseases or symptoms selected from the group comprising chronic pain, asthma, diabetes, risk of heart attack, withdrawal symptoms when quitting Smoking and Parkinson's disease.

23. Use p, characterized in that the said active substance or at least one of these active substances are selected from the group including analgesics, protivobloshinye tools, antidiabetics, vasodilator, anti-withdrawal and anti-Parkinsonian funds.



 

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15 cl, 9 dwg, 2 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: invention is related to new compounds of formula (I): , in which: Ra and Ra', identical or different, mean atom of hydrogen or alkyl, R1 means atom of hydrogen or alkyl, cycloalkyl, heterocycloalkyl or aryl, R2 means group of formula -(CH2)x-(CO)y-Y or -(CO)y-(CH2)x-Y, in which, x = 0, 1, 2, 3 or 4, y = 0 or 1, Y means atom of hydrogen or the following group: hydroxyl, alkyl, cycloalkyl, alkyloxyl, aryl, heteroaryl or -NR11R12, besides, Y is not an atom of hydrogen, when x=y=0, R11 and R12, identical or different, mean atom of hydrogen or the following group: alkyl, cycloalkyl, alkyloxyl or -NR13R14, or R11 and R12 together with atom of nitrogen, to which they are connected, create mono- or bicyclic structure, which contains 4-10 links and unnecessarily contain additionally 1-3 heteroatoms and/or 1-3 ethylene unsaturated links, besides this cycle is not necessarily substituted in any of positions with 1-3 groups, selected from atoms of halogen and hydroxyl, alkyl, cycloalkyl and alkyloxygroups; R13 and R14, identical or different, mean atom of hydrogen or alkyl, R3 means 1-3 groups, identical or different, available in any position of cyclic structure, to which they are connected, and selected from atoms of halogen; R5 means atom of hydrogen, R4 is selected from groups of formulae (a), (b), (c), which are not necessarily substituted with aryl group, described below: (a), (b), (c), in which p=0,1,2 or 3; m=0,1 or 2, and either a) X means link -N(R10)-, in which R10 is selected from: -CO-alkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-aryl, -CO-heteroaryl, - or R10 with atom of nitrogen, with which it is connected, and with atom of carbon, available in any position of cyclic structure of formula (a), but not with neighboring to mentioned atom of nitrogen, creates bridge, containing 3-5 links, or, b) X means link -C(R6)(R7)-, where R6 is selected from the following: atom of hydrogen, atom of halogen, group -(CH2)x-OR8, -(CH2)x-NR8R9, -(CH2)x-CO-NR8R9 or -(CH2)x-NR8-COR9, in which x=0,1,2,3 or 4, alkyl, cycloalkyl, heterocycloalkyl, aryl, heterocycloalkyl, condensed with aryl, besides, alkyl, cycloalkyl or aryl groups are not necessarily substituted with 1 or several groups, selected from groups: R, R', -OR, -NRR', -COR; R7 is selected from atoms of hydrogen and halogen and the following groups: alkyls, -OR, -NRR', -NR-CO-R', -NR-COOR', -R8 and R9 are selected, independently from each other, from atom of hydrogen and the following groups: alkyls, cycloalkyls, aryls, -CO-alkyls, besides, alkyls and aryls are unnecessarily substituted with one or several groups, selected from groups: R, R', -OR, or R8 and R9 together create heterocycloalkyl,- R and R' mean, independently from each other, atom of hydrogen or alkyl, cycloalkyl, besides, mentioned hetero aryl groups represent aromatic groups, including from 5 to 10 links and including from 1 to 4 heteroatoms, such as atom of nitrogen, oxygen and/or sulfur; besides mentioned heterocycloalkyl groups represent cycloalkyl groups, including from 5 to 6 links and including from 1 to 4 heteroatoms, such as atom of nitrogen, oxygen or sulfur; in the form of base or acid-additive salt, and also in the form of hydrate or solvate. Invention is also related to medicinal agent, to pharmaceutical composition, to application, to method of production, and also to compounds of formulas (VI), (XVIII), (XIX).

EFFECT: new biologically active compounds have activity of agonists of melanocortin receptors.

27 cl, 16 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention is related to new compounds that comply with formula (I) , where: n is equal to 1, Ra, Ra', Rb, Rb', identical or different, mean atom of hydrogen or alkyl or cycloalkyl group, besides, Rb and Rb' may create carbon bridge having 4 links together with hydrogen atoms of cycle, to which they are connected, R1 means cyclohexyl group, R2 means 1,2,4-triazolyl group, R3 means 1-3 groups, selected from atoms of halogen, available in any position of cycle, to which they are connected, R5 means atom of hydrogen, R4 is selected from groups of formulas (a), (b) and (c), given below, mono- or polysubstituted with aryl group: (a), (b), (c), in which: p=0, 1, 2 or 3, m=0, 1 or 2, and either a) X means link -N(R10)-, where R10 is selected from: groups -CO-NR8R9, -COOR8, -(CH2)x-OR8, -(CH2)x-COOR8, -(CH2)x-COR8, in which x=1, 2, 3 or 4, heterocycloalkyl group, condensed with aryl group, cycloalkyl, aryl, heteroaryl, alkylaryl, -CO-alkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-aryl, -CO-heteroaryl, -CO-alkylaryl, -SO2-alkyl, -SO2-cycloalkyl, -SO2-aryl, besides, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are unnecessarly substituted with one or several groups selected from atoms of halogen and groups R, R', OR, NRR', -CN, -COOR, COR; or R10 together with atom of nitrogen, to which it is connected, and with atom of carbon, available in any position of cyclic structure of formula (a), but not in neighboring position to mentioned atom of nitrogen, creates a bridge that contains 3-5 links, R8 and R9 are selected, independently from each other, from atom of hydrogen and alkyl or cycloalkyl groups; R and R' mean, independently from each other, atom of hydrogen or alkyl, cycloalkyl, aryl groups; or b) X means link - C(R6)(R7)-, where R6 is selected from the following: atom of hydrogen, atom of halogen, groups -(CH2)x-OR8, -(CH2)x-COOR8, -(CH2)x-NR8R9, -(CH2)x-CO-NR8R9 or -(CH2)x-NR8-COR9, in which x=0, 1, 2, 3 or 4, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl group, heterocycloalkyl group, condensed or non-condensed, available in spiro-position to cycle of formula (a), to which it is connected, heterocycloalkyl group, condensed with aryl group, besides, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are unnecessarily substituted with one or several groups selected from atoms of halogen and groups R, R', OR, NRR', -CO-NRR', -CN, -COOR, OCOR, COR, NRCOOR'; and heterocycloalkyl groups are unnecessarily condensed with aryl group; R7 is selected from atoms of hydrogen and halogen and alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl groups, -OR, -O-aryl, -O-alkylaryl, -O-alkylheteroaryl, groups -NRR', -CO-NRR', -NR-CO-R', -NR-CO-NRR', -NR-COOR', -NO2, -CN and -COOR, R8 and R9 are selected, independently from each other, from atom of hydrogen and alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl groups, -CO-alkyl, -CO-cycloalkyl, -CO-aryl, -(CH2)x-OR, where x=0, 1, 2, 3 or 4, besides, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are unnecessarily substituted with one or several groups selected from atoms of halogen and groups R, R', OR, NRR', -CO-NRR', -CN, -COOR, OCOR, COR, NRCOOR'; or R8 and R9 create together cycloalkyl or heterocycloalkyl; R and R' mean, independently from each other, atom of hydrogen or alkyl, cycloalkyl, heterocycloalkyl, aryl, or may together create cycloalkyl or heterocycloalkyl; besides heteroaryl group represents aromatic group that contains from 5 to 10 atoms and from 1 to 4 heteroatoms, selected from nitrogen, oxygen or sulfur; heterocycloalkyl group represents cycloalkyl group, which contains from 5 to 10 atoms and contains from 1 to 4 heteroatoms selected from nitrogen, oxygen or sulfur; in the form of base or acid-additive salt, and also in the form of hydrate or solvate. Invention is also related to medicinal agent, to pharmaceutical composition, to application, to method of production, and also to compounds of formulas (IV) , (V), (VI), (XXVIII), (XXIX), (II).

EFFECT: production of new biologically active compounds, having activity of agonists of melanocortin receptors.

36 cl, 22 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: there are described derivatives of 1,3,4-oxadiazol-2-one of formula I and their pharmaceutically acceptable salts wherein ARYL represents phenyl which can have one substitute chosen from halogen; W represents chain or (CH2)m where m designates an integer 1 to 4; Z represents -O(CH2)n-, -(CH2)n-Y-(CH2)n- where Y designates O, n independently means an integer 1 to 5; X represents O or S; R1 represents C1-6 alkyl; R2 represents substituted phenyl where substitutes are chosen from the group including C1-6alkyl, C1-4perfluoralkyl. There are also described pharmaceutical composition, and method of treating a disease in mammal wherein said disease can be modulated by PPAR-delta receptor binding activity.

EFFECT: compounds possess agonist or antagonist activity with respect to PPAR-delta receptor.

9 cl, 2 tbl, 34 ex

FIELD: medicine.

SUBSTANCE: invention refers to new compounds of formula: I where R1 represents hydrogen or C1-7-alkyl; R2 and R3 independently represent hydrogen; R4 and R5 independently represent hydrogen; R6, R7, R8 and R9 independently represent hydrogen, C1-7-alkyl; and one of R6, R7 and R8 represents where R10 represents hydrogen, C1-7-alkyl; R11 represents hydrogen, C1-7-alkyl; one of R12 or R13 represents hydrogen, C1-7-alkyl or fluorine-C1-7-alkyl; and the other represents undivided electron pair; R14 represents hydrogen, C1-7-alkyl, halogen; R15 represents aryl or aryl substituted with 1-3 groups chosen from C1-7-alkyl C1-7-alkoxy, halogen, fluorine-C1-7-alkyl and fluorine-C1-7-alkoxy; and n has a value 1, 2 or 3; and to all their enantiomers and to pharmaceutically acceptable salts and/or esters. The invention also concerns the pharmaceutical compositions.

EFFECT: production of new biologically active compounds with agonist activity with respect to PPARδ and PPARα.

20 cl, 25 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: compounds can be used for treatment and prevention of diseases associated with activity of specified enzyme, such as diabetes, obesity, diseases associated with food intake, dyslipidemia and hypertension. In general formula (I) , R1 represents methyl, ethyl, cyclopropyl, cyclobutyl, isopropyl, tert-butyl, methoxymethyl, cyclopropyl methoxymethyl, 2-methyl thiazolyl, morpholinyl methyl or phenyl; R2 represents hydrogen, C1-4alkyl or phenyl; R3 represents hydrogen, C1-4alkyl or phenyl; R4 represents phenyl, naphthyl, thiophenyl, quinolyl or piperidyl where phenyl, naphthyl, thiophenyl, quinolyl and piperidyl are optionally substituted with one to three substitutes independently chosen of C1-4alkyl, halogen, C1-4alkoxy, cyano, trifluoromethyl, phenyl, phenyls C1-4alkyl, phenyloxy, oxasolyl and pyridinyl; R5 represents hydrogen, C1-4alkyl, phenyl-C1-4alkyl, C3-6dicloalkyl-C1-4alkyl or aminocarbonylC1-4alkyl.

EFFECT: higher clinical effectiveness.

17 cl, 2 dwg, 72 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I), their R and S isomers; or a mixture of R and S isomers; or pharmaceutically acceptable salts. Disclosed compounds can be used as a medicinal agent with agonist properties towards PPAR. In formula (I) and L represents (II) or (III); R1, R2, R3, Ya, R4a, R", Yb, R4b are hydrogen; R and R' are independently hydrogen, C1-C4alkoxy; n equals 0, 1 or 2; m equals 0, 1 or 2; X1 is a -Z-(CH2)P-Q-W group; X2 is -CH2-, -C(CH3)2-, -O- or -S-.

EFFECT: invention relates to a pharmaceutical composition, which contains the disclosed compound, to use of the pharmaceutical composition as a medicinal agent, to use of the disclosed compound in making the pharmaceutical composition.

13 cl, 35 ex

FIELD: chemistry.

SUBSTANCE: object of present invention is the following compounds: thiazol-2-ylamide 2-(3,4-dichlorophenoxy) hexanoic acid, 2-(4-fluorophenoxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(4-methoxyphenoxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(4-methoxyphenoxy)-K-pyridin-2-ylhexaneamide, 2-(3,4-dichlorophenoxy)-4-methyl-N,3-thiazol-2-ylpentaneamide, 2-(1,1'-biphenyl-4-yloxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(4-isopropylphenoxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(3-methoxyphenoxy)-N-1,3-thiazol-2-ylhexaneamide, and others, named in the formula of invention. Present invention also relates to a pharmaceutical composition, which contains the invented compound as an active ingredient and use of compounds in preparing a medicinal agent which increases activity of glucose. The invention also pertains to a compound of formula (I) where G is -C(O)-; L1 is a direct bond, A is >N-, X is a direct bond, R1 is cyclohexyl, R3 is cyclohexyl, substituted with R34, R4 is hydrogen; R5 is thiazol-5-yl, substituted with R48.

EFFECT: obtaining compounds which can be used for preparing a medicinal agent which can be used for treating diseases caused by glucokinase deficiency, for preparing a medicinal agent for treating diseases where increased activity of glucokinase is favourable.

6 cl, 143 ex

FIELD: chemistry.

SUBSTANCE: in compounds of formula (I) , Q is: (IIa) or (IIb) , R1 is chosen from a group which consists of carboxylic aryl and carboxylic aryl which is substituted with substitute(s) independently chosen from a group which consists of halogen, cyano, nitro, C1-10alkyl, C1-10alkyl which is substituted with substitute(s) independently chosen from a group which consists of halogen, C1-9alkoxy, C1-9alkoxy which is substituted with substitute(s) independently chosen from a group which consists of halogen, mono-C1-5alkylamino, and heterocyclyl or heterocyclyl which is substituted with substitute(s) independently chosen from a group which consists of halogen, C1-5alkyl; R2 is C1-5alkyl, C1-5alkyl which is substituted with halogen, C1-5alkyl which is substituted with carboxylic aryl, C1-5alkoxy, -N(R2a)(R2b); where R2a and R2b are each independently hydrogen, C1-5alkyl or C1-5alkyl, substituted with substitute(s) independently chosen from a group which consists of hydroxyl, carboxylic aryl; L represents formula (IIIa); , where R3 and R4 are each hydrogen; A is a single bond, and B is a single bond or -CH2-; Z1, Z3, and Z4 are each independently hydrogen, halogen, C1-5alkyl, C1-5alkyl, substituted with carboxylic aryl, C1-5alkoxy, mono-C1-5alkylamino, di-C1-5alkylamino, carboxylic aryl, heterocyclyl or substituted heterocyclyl; Z2 is hydrogen, C1-5alkyl, C1-5alkyl which is substituted with carboxylic aryl, C1-5alkoxy, mono-C1-5alkylamino, di-C1-5alkylamino, carboxylic aryl, heterocyclyl or substituted heterocyclyl; Y is -C(O)NH-, -C(O)-, -C(S)NH-, -C(O)O- or -CH2-; where carboxylic aryl is phenyl; heterocyclyl is 1H-indolyl, 9H- xanthenyl, benzo[1,3]dioxolyl, furyl, imidazolyl, isoxazolyl, morpholinyl, piperazinyl, pyridyl, pyrrolidyl; halogen is fluorine, chlorine, bromine or iodine. The invention also relates to a pharmaceutical composition.

EFFECT: compounds can be used for treating central nervous system diseases, and for improving memory functioning, sleep, awakening, diabetes.

16 cl, 8 dwg, 4 tbl, 525 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula (I) , in which Ar is furanyl, thiophenyl, thiazolyl, pyridinyl; R1 is independently chosen from a group consisting of hydrogen, lower alkyl, lower alkoxy, halogen and nitro; R2 is independently chosen from a group consisting of hydrogen and halogen; R4 is hydroxyl or residue of pyrrolidine-2-carboxylic acid, piperidine-2-carboxylic acid or 1-aminocyclopentane carboxylic acid, bonded through a nitrogen atom of an amino acid residue; n is 0, 1, 2, 3, 4 or 5; m is 0, 1, 2, 3 or 4; p is 0, and s is 0, or to their pharmaceutically acceptable salts, under the condition that, the compound is not S-1- [5-(biphenyl-4-yloxymethyl)furan-2-carbonyl]pyrrolidin-2-carboxylic acid, 5-(biphenyl-4-yloxymethyl)furan-2-carboxylic acid, 3-(biphenyl-4-yloxymethyl)benzoic acid, 2-(biphenyl-3-yloxymethyl)benzoic acid, 4-(biphenyl-3-yloxymethyl)benzoic acid, 4-(biphenyl-4-yloxymethyl)benzoic acid, 5-(biphenyl-4-yloxymethyl)thiophene-2-carboxylic acid. Invention also relates to a pharmaceutical composition based on formula (I) compounds, which stimulates glycogen synthase activity.

EFFECT: wider range of use of the compounds.

27 cl, 34 ex, 8 dwg

FIELD: medicine.

SUBSTANCE: invention is related to new compounds of formula (I): , in which: Ra and Ra', identical or different, mean atom of hydrogen or alkyl, R1 means atom of hydrogen or alkyl, cycloalkyl, heterocycloalkyl or aryl, R2 means group of formula -(CH2)x-(CO)y-Y or -(CO)y-(CH2)x-Y, in which, x = 0, 1, 2, 3 or 4, y = 0 or 1, Y means atom of hydrogen or the following group: hydroxyl, alkyl, cycloalkyl, alkyloxyl, aryl, heteroaryl or -NR11R12, besides, Y is not an atom of hydrogen, when x=y=0, R11 and R12, identical or different, mean atom of hydrogen or the following group: alkyl, cycloalkyl, alkyloxyl or -NR13R14, or R11 and R12 together with atom of nitrogen, to which they are connected, create mono- or bicyclic structure, which contains 4-10 links and unnecessarily contain additionally 1-3 heteroatoms and/or 1-3 ethylene unsaturated links, besides this cycle is not necessarily substituted in any of positions with 1-3 groups, selected from atoms of halogen and hydroxyl, alkyl, cycloalkyl and alkyloxygroups; R13 and R14, identical or different, mean atom of hydrogen or alkyl, R3 means 1-3 groups, identical or different, available in any position of cyclic structure, to which they are connected, and selected from atoms of halogen; R5 means atom of hydrogen, R4 is selected from groups of formulae (a), (b), (c), which are not necessarily substituted with aryl group, described below: (a), (b), (c), in which p=0,1,2 or 3; m=0,1 or 2, and either a) X means link -N(R10)-, in which R10 is selected from: -CO-alkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-aryl, -CO-heteroaryl, - or R10 with atom of nitrogen, with which it is connected, and with atom of carbon, available in any position of cyclic structure of formula (a), but not with neighboring to mentioned atom of nitrogen, creates bridge, containing 3-5 links, or, b) X means link -C(R6)(R7)-, where R6 is selected from the following: atom of hydrogen, atom of halogen, group -(CH2)x-OR8, -(CH2)x-NR8R9, -(CH2)x-CO-NR8R9 or -(CH2)x-NR8-COR9, in which x=0,1,2,3 or 4, alkyl, cycloalkyl, heterocycloalkyl, aryl, heterocycloalkyl, condensed with aryl, besides, alkyl, cycloalkyl or aryl groups are not necessarily substituted with 1 or several groups, selected from groups: R, R', -OR, -NRR', -COR; R7 is selected from atoms of hydrogen and halogen and the following groups: alkyls, -OR, -NRR', -NR-CO-R', -NR-COOR', -R8 and R9 are selected, independently from each other, from atom of hydrogen and the following groups: alkyls, cycloalkyls, aryls, -CO-alkyls, besides, alkyls and aryls are unnecessarily substituted with one or several groups, selected from groups: R, R', -OR, or R8 and R9 together create heterocycloalkyl,- R and R' mean, independently from each other, atom of hydrogen or alkyl, cycloalkyl, besides, mentioned hetero aryl groups represent aromatic groups, including from 5 to 10 links and including from 1 to 4 heteroatoms, such as atom of nitrogen, oxygen and/or sulfur; besides mentioned heterocycloalkyl groups represent cycloalkyl groups, including from 5 to 6 links and including from 1 to 4 heteroatoms, such as atom of nitrogen, oxygen or sulfur; in the form of base or acid-additive salt, and also in the form of hydrate or solvate. Invention is also related to medicinal agent, to pharmaceutical composition, to application, to method of production, and also to compounds of formulas (VI), (XVIII), (XIX).

EFFECT: new biologically active compounds have activity of agonists of melanocortin receptors.

27 cl, 16 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives (indole-3-yl)heterocyclic compounds of formula 1: , where: A represents 5-member aromatic heterocyclic ring, where X1, X2 and X3 are independently selected from N, O, S, CR; R means H, (C1-4)alkyl; or R, when it is available in X2 or X3, may form 5-8-member ring together with R3; R1 means 5-8-member saturated carbocyclic ring, which unnecessarily contains heteroatom O; R2 means H; or R2 is connected to R7 with creation of 6-member ring, which unnecessarily contains heteroatom O, or where mentioned heteroatom is connected to position 7 of indole ring; R3 and R4 independently mean H, (C1-6)alkyl, which is unnecessarily substituted with OH, (C1-4)alkyloxy; or R3 together with R4 and N, with which they are connected, creates 4-8-member ring, which unnecessarily contains additional heteroatom, selected from O and S, and unnecessarily substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy or (C1-4)alkyloxy-(C1-4)alkyl; or R3 together with R5 creates 4-8-member ring, unnecessarily substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy; or R3 together with R, when present in X2 or X3, creates 5-8-member ring; R5 means H; or R5 together with R3 creates 4-8-member ring, unnecessarily substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy; R5' means H; R6 means one substituent selected from H, (C1-4)alkyl, (C1-4)alkyloxy, halogen; R7 means H, (C1-4)alkyl, (C1-4)alkyloxy, halogen; or R7 is connected to R2 with creation of 6-member ring, which unnecessarily contains additional heteroatom O, and where heteroatom is connected to position 7 of indole ring; or its pharmaceutically acceptable salt. Compounds of formula I display activity of agonists to cannabinoid receptor CB1.

EFFECT: possibility to use them for treatment of pains of various nature.

10 cl, 1 tbl, 42 ex

FIELD: medicine.

SUBSTANCE: invention is related to new compounds that comply with formula (I) , where: n is equal to 1, Ra, Ra', Rb, Rb', identical or different, mean atom of hydrogen or alkyl or cycloalkyl group, besides, Rb and Rb' may create carbon bridge having 4 links together with hydrogen atoms of cycle, to which they are connected, R1 means cyclohexyl group, R2 means 1,2,4-triazolyl group, R3 means 1-3 groups, selected from atoms of halogen, available in any position of cycle, to which they are connected, R5 means atom of hydrogen, R4 is selected from groups of formulas (a), (b) and (c), given below, mono- or polysubstituted with aryl group: (a), (b), (c), in which: p=0, 1, 2 or 3, m=0, 1 or 2, and either a) X means link -N(R10)-, where R10 is selected from: groups -CO-NR8R9, -COOR8, -(CH2)x-OR8, -(CH2)x-COOR8, -(CH2)x-COR8, in which x=1, 2, 3 or 4, heterocycloalkyl group, condensed with aryl group, cycloalkyl, aryl, heteroaryl, alkylaryl, -CO-alkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-aryl, -CO-heteroaryl, -CO-alkylaryl, -SO2-alkyl, -SO2-cycloalkyl, -SO2-aryl, besides, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are unnecessarly substituted with one or several groups selected from atoms of halogen and groups R, R', OR, NRR', -CN, -COOR, COR; or R10 together with atom of nitrogen, to which it is connected, and with atom of carbon, available in any position of cyclic structure of formula (a), but not in neighboring position to mentioned atom of nitrogen, creates a bridge that contains 3-5 links, R8 and R9 are selected, independently from each other, from atom of hydrogen and alkyl or cycloalkyl groups; R and R' mean, independently from each other, atom of hydrogen or alkyl, cycloalkyl, aryl groups; or b) X means link - C(R6)(R7)-, where R6 is selected from the following: atom of hydrogen, atom of halogen, groups -(CH2)x-OR8, -(CH2)x-COOR8, -(CH2)x-NR8R9, -(CH2)x-CO-NR8R9 or -(CH2)x-NR8-COR9, in which x=0, 1, 2, 3 or 4, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl group, heterocycloalkyl group, condensed or non-condensed, available in spiro-position to cycle of formula (a), to which it is connected, heterocycloalkyl group, condensed with aryl group, besides, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are unnecessarily substituted with one or several groups selected from atoms of halogen and groups R, R', OR, NRR', -CO-NRR', -CN, -COOR, OCOR, COR, NRCOOR'; and heterocycloalkyl groups are unnecessarily condensed with aryl group; R7 is selected from atoms of hydrogen and halogen and alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl groups, -OR, -O-aryl, -O-alkylaryl, -O-alkylheteroaryl, groups -NRR', -CO-NRR', -NR-CO-R', -NR-CO-NRR', -NR-COOR', -NO2, -CN and -COOR, R8 and R9 are selected, independently from each other, from atom of hydrogen and alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl groups, -CO-alkyl, -CO-cycloalkyl, -CO-aryl, -(CH2)x-OR, where x=0, 1, 2, 3 or 4, besides, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are unnecessarily substituted with one or several groups selected from atoms of halogen and groups R, R', OR, NRR', -CO-NRR', -CN, -COOR, OCOR, COR, NRCOOR'; or R8 and R9 create together cycloalkyl or heterocycloalkyl; R and R' mean, independently from each other, atom of hydrogen or alkyl, cycloalkyl, heterocycloalkyl, aryl, or may together create cycloalkyl or heterocycloalkyl; besides heteroaryl group represents aromatic group that contains from 5 to 10 atoms and from 1 to 4 heteroatoms, selected from nitrogen, oxygen or sulfur; heterocycloalkyl group represents cycloalkyl group, which contains from 5 to 10 atoms and contains from 1 to 4 heteroatoms selected from nitrogen, oxygen or sulfur; in the form of base or acid-additive salt, and also in the form of hydrate or solvate. Invention is also related to medicinal agent, to pharmaceutical composition, to application, to method of production, and also to compounds of formulas (IV) , (V), (VI), (XXVIII), (XXIX), (II).

EFFECT: production of new biologically active compounds, having activity of agonists of melanocortin receptors.

36 cl, 22 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: invention is related to derivatives of isothiourea of formula I, including their pharmaceutically acceptable salts, which possess properties of antagonist CXCR4. In compounds of formula I , where R1 means remainder of formula (a) , (b) or (c) , R2 means -(CR22R23)1-3-, R3 and R8 each means S, R4 and R5 each independently means C3-C12cycloalkyl, C1-C12alkyl or saturated C8-C12 polycyclic hydrocarbon remainder, such as adamantine, non-substituted phenyl or non-substituted benzyl unnecessarily substituted with group R25, R6 means H or C1-C6alkyl, R7 means CH, R9 means direct connection or -(CR22R23)1-2-, R10-R15 each means H, R16-R23 each independently means H, C1-C6alkyl, or R20 and R21 together with carbon atoms, to which they are connected, create a benzene ring, and R25 has one of values given above for R16-R23.

EFFECT: improved method for production of derivatives of isothiourea.

5 cl, 1 tbl, 24 ex

FIELD: medicine.

SUBSTANCE: invention relates to a method of producing 2-amino-2-[2-[4-(3-benzyloxy-phenylthio)-2-chlorophenyl]ethyl]-1,3-propanediol hydrochloride or its hydrate, involving the following steps: reacting 4-(3-benzyloxyphenylthio)-2-chlorobenzaldehyde and diethylphosphonoacetate ethyl in a solvent in the presence of a base, obtaining ethyl 3-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]acrylate; reducing the formed ethyl 3-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]acrylate with subsequent mesylation, iodizing, and nitration, obtaining 1-benzyloxy-3-[3-chloro-4-(3-nitropropyl-phenylthio]benzol; hydroxymethylation of the formed 1-benzyloxy-3-[3-chloro-4-(3-nitropropyl-phenylthio] benzol with formaldehyde, obtaining 2-[2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl]-2-nitro-1,3-propanediol; as well as reduction of the formed 2-[2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl]-2-nitro-1,3-propanediol, obtaining the end product. The invention also relates to intermediate products: ethyl 3-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]acrylate, 1-benzyloxy-3-[3-chloro-4-(3-nitropropylphenylthio]benzol, 2-[2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl]-2-nitro-1,3-propanediol or to their hydrates.

EFFECT: industrial production of said compound with good output and high purity.

4 cl, 4 ex

FIELD: medicine.

SUBSTANCE: carboxylic acid compounds are presented by formula (I) where R1 represents (1) hydrogen atom, (2) C1-4alkyl; E represents -CO-; R2 represents (1) halogen atom, (2) C1-6 alkyl, (3) trihalogen methyl; R3 represents (1) halogen atom, (2) C1-6alkyl; R4 represents (1) hydrogen atom; R5 represents (1) C1-6alkyl; represents phenyl; G represents (1) C1-6alkylene; represents 9-12-merous bicyclic heterocycle containing heteroatoms, chosen of 1-4 nitrogen atoms, one or two oxygen atoms; m represents 0 or an integer 1 to 4, n represents 0 or an integer 1 to 4, and i represents 0 or an integer 1 to 11 where R2 can be identical or different provided m is equal to 2 or more, R3 can be identical or different provided n is equal to 2 or more, and R5 can be identical or different provided i is equal to 2 or more; both R12 and R13, independently represent (1) C1-4alkyl, (2) halogen atom, (3) hydroxyl or (4) hydrogen atom, or R12 and R13 together represent (1) oxo or (2) C2-5alkylene and where provided R12 and R13 simultaneously represent hydrogen atom, carboxylic acid compound presented by formula (I), represents a compound chosen from the group including the compounds (1) - (32), listed in cl.1 of the patent claim. Besides the invention concerns a pharmaceutical composition based in the compound of formula I and to application of the compound of formula I for making the pharmaceutical composition.

EFFECT: there are produced new carboxylic acid derivatives with antagonistic activity with respect to DP receptor.

14 cl, 74 ex

FIELD: medicine.

SUBSTANCE: claimed invention relates to pharmaceutical medicinal forms, which are applied for controlled and/or directed delivery of active substance to definite part of gastrointestinal tract of human or animals. Pharmaceutical medicinal forms preferably include active substance N-(2-(2-phthalimidoetoxy)acetyl)-L-alanyl-D-glutamic acid (LK 423).

EFFECT: also described are methods of treating chronic inflammatory diseases of gastrointestinal tract of human and/or animals applying pharmaceutical medicinal forms of claimed invention.

21 cl, 5 ex, 3 tbl, 7 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to new quinazolinone derivatives of formula I in form of a free base or acid addition salt, with agonist properties towards cannabinoid (CB) receptor. The compounds can be used for treating or preventing diseases or conditions, where cannabinoid receptor plays a role or is activated, particularly eye diseases, for example glaucoma. In compounds of formula I

R1, R2, R3, R4 and R5 are independently hydrogen; halogen; C1-C4alkyl, which is optionally substituted with C1-C4alkoxycarbonyl; C3-C7cycloalkyl; C3-C7cycloalkylC1-C4alkyl; C1-C4alkylcarboxy; SO2R10; cyano; -SO2N(R10)R11; -S-R10 or -SOR10; or R1 and R2 or R2 and R3, together with carbon atoms to which they are bonded, form an aromatic or aliphatic carbocyclic group with 5 to 10 ring atoms, or an aromatic or aliphatic heterocyclic group, with 5 to 10 ring atoms, from which one, two or three heteroatoms are selected from nitrogen, oxygen and sulphur; R6 is -CH2-O-C(O)-N(R12)R13, -CH2-X-C(O)-R14, C1-C4alkyl or hydroxyC1-C4alkyl; R7, R8 and R9 are independently C1-C4alkyl; R10 and R11 are independently hydrogen, C1-C4alkyl; C2-C4alkenyl; C3-C7cycloalkyl; C3-C7cycloalkylC1-C4alkyl; C1-C4alkoxyC1-C4alkyl; C1-C4alkylcarboxy; hydroxyC1-C4alkoxyC1-C4alkyl; hydroxy; hydroxyC1-C4alkyl; phenylC1-C4alkyl which are optionally substituted with hydroxy, C1-C4alkoxy, carboxy, C1-C4alkoxycarbonylC1-C4alkyl, C1-C4alkoxycarbonyl, cyano; or R10 and R11 together form an aliphatic heterocyclic group, with 5 to 10 ring atoms, from which one, two or three heteroatoms are selected from nitrogen, oxygen and sulphur; R12 and R13 are independently hydrogen, C1-C4alkyl, C2-C4alkenyl, C3-C7cycloalkyl, C3-C7cycloalkylC1-C4alkyl, C1-C4alkoxyC1-C4alkyl, hydroxyC1-C4alkoxyC1-C4alkyl, hydroxyC1-C4alkyl, dihydroxyC1-C4alkyl, C1-C4alkoxycarbonylC1-C4alkyl, C1-C4alkoxycarbonyl, cyano, -SO2R10, -SO2N(R10)R11, -S-R10, -SOR10, -C1-C4-alkylene-NH-SO2R10, C1-C4-alkylene-SOR10, -C1-C4-alkylene-NH-SO2R10, -C1-C4-alkylene-CON(R10)R11, -CON(R10)R11, -C1-C4-alkylene-C(O)OR10, fluoroalkyl, or R12 and R13 form a substituted or unsubstituted aliphatic heterocyclic group, with 5 to 10 ring atoms, where the substitutes are selected from a group which consists of hydroxymethyl, hydroxy or oxo group; R14 is NH, C1-C4alkyl-NH-, C2-C4alkenyl-NH-, C3-C7cyclalkyl-NH-, C3-C7cycloalkylC1-C4alkyl-NH-, C1-C4alkoxyC1-C4alkyl-NH-, hydroxyC1-C4alkoxyC1-C4alkyl-NH-, hydroxyC1-C4alkyl-NH-, dihydroxyC1-C4alkyl-NH-, C1-C4alkoxycarbonylC1-C4alkyl-NH-, C1-C4alkoxycarbonyl-NH-, -NH-C1-C4-alkylene-CN, -NH-SO2R10, -NH-SO2N(R10)R11, -NH-C1-C4-alkylene-S-R10, -NH-SOR10, -NH-C1-C4-alkylene-SO2R10, -NH-C1-C4-alkylene-SOR10, -NH-C1-C4-alkylene-NH-SO2R10, -NH-C1-C4-alkylene-CON(R10)R11, -NH-CON(R10)R11, -NH-C1-C4-alkylene-C(O)OR10, -NH-fluoroalkyl or unsubstituted aliphatic heterocyclic group, with 5 to 10 ring atoms; X is O or CH2.

EFFECT: obtaining new quinazolinone derivatives of formula I in form of a free base or acid addition salt, with agonist properties towards cannabinoid (CB) receptor.

16 cl, 112 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, specifically to new compounds (1Z,3Z)-4-aryl-4-hydroxy-1-(3,3-dialkyl-3,4-dihydroisoquinolin-1(2N)-ylidene)-but-3-en-4-ones with general formula:

III: R=H, Alk1=Alk2=Me, Ar=Ph (a), Ar=C6H4Me-p (b), Alk1=Me, Alk2=Bu, Ar=Ph (c), Ar=C6H4Me-p (d), R=OMe, Alk1=Alk2=Me, Ar=Ph (e), Ar=C6H4Me-p (f), R=OEt, Alk1=Alk2=Me, Ar=Ph (g). The invention also relates to a method of producing said compounds.

EFFECT: obtaining new compounds with analgetic activity and which can be used as primary products in synthesis of new heterocyclic systems.

4 cl, 1 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new derivatives of imidazo[1,2-c]pyrimidinyl acetic acid of formula (I) or to its salts: , where R1 is ,, in which n is an integer ranging from 0 to 6; Y is aryl, where the said aryl is optionally substituted at a substitutable position with one or more substitutes selected from a group which consists of halogen or C1-6alkyl, optionally substituted with mono-, di- or trihalogen; R2 is hydrogen; R3 is hydrogen or halogen; and R4 is hydrogen. The invention also relates to derivatives of imidazo[1,2-c]pyrimidinyl acetic acid of formula (I-i) or to its salts, to a drug, to use of compounds in paragraph 1, as well as to a drug in form of a standard single dosage.

EFFECT: obtaining new biologically active compounds, which are active towards CRTH2.

23 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new 2-alkylsufanyl-3-arylsufonyl-cycloalkano[e]pyrazolol[1,5-a]pyrimidines of general formula 1 or 2-alkylsufanyl-3-arylsufonyl-cycloalkano[d]pyrazolo[1,5-a]pyrimidines of general formula 2, which are antagonist of 5-HT6 receptors. In compounds of formula 1

and 2 ,

R1 is a hydrogen atom or C1-C3 alkyl; R2 is C1-C3 alkyl; R3 is a hydrogen atom, one or two optionally identical halogen atoms, C1-C3 alkyl or hydroxyl, optionally substituted with C1-C3 alkyl; n is an integer equal to 1, 2 or 3.

EFFECT: compounds can be used in preventing and treating diseases of the central nervous system, anxiolytics and as compounds with nootropic effect and suitable for enhancing memory.

12 cl, 1 dwg, 4 tbl, 9 ex

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