1-aryl-3-aminoalkoxypyrazol as sigma ligands intensifying analgesic action of opioids and relieving addiction thereto

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are presented: a combination possessing analgesic action of at least one sigma ligand and at least one opioid or opiate compound specified in morphine and its structural derivatives, phentanyl and tramadol for simultaneous, separate or sequential administration; the sigma ligand has the general formula ;

using it for preparing a therapeutic agent potentiating analgesic action of morphine or its structural derivatives, phentanyl and tramadol and/or relieving addiction thereto. What is also presented is using the combination of at least one sigma ligand and at least one opioid or opiate compound for preparing the therapeutic agent for potentiating analgesic action of opioids or opiates and for relieving addiction thereto; the opiate is specified in a group of: hydromorphone, oxymorphone, desomorphine, diacetylmorphine, nicomorphine, dipropanoylmorphine, benzylmorphine and ethylmorphine.

EFFECT: what is shown is the synergetic analgesic action of the morphine and compound 63 combination; the compound appeared to relieve the effects of positive stimulation caused by morphine with establishment of behaviour reflex.

16 cl, 10 dwg

 

The SCOPE of the INVENTION

This invention relates to the enhancement of analgesic effect of opioids and opiates, as well as the weakening of attachment to him. More specifically, this invention relates also to the use of the group of ligands of Sigma receptors to enhance the analgesic effect of opioids and opiates, and at the same time to reduce dependence caused by them.

BACKGROUND of INVENTION

Opioids and opioids are strong analgesics, commonly used in clinical practice. Opioid and opiate drugs are classified generally by the selectivity of their binding to cellular receptors and receptors in differentiated tissues, which are associated with specific types of medicines as a ligand. These receptors include mu (μ), Delta (δ), Kappa (κ) and nociceptive receptors.

A well-known narcotic opioids, such as morphine and its analogues are selective for opioid mu-receptor. Mu-receptors mediate analgesia, suppression of respiration and inhibition of passage of food through the stomach and intestines. Kappa receptors mediate analgesia and sedation. However, despite their good activity as analgesics, opioids and opiates have a negative side, since they cause dependency.

Sigma is eceptor are non-receptor type of great interest to pharmacology, thanks to their role in the processes associated with anesthesia. Linking Sigma-sites are preferred affinity to Pervouralsk isomers of some opiate benzomorphans, such as (+)SKF 10047, (+)cyclazocine and (+)pentazocine, and in respect of such narcoleptics as haloperidol. Sigma receptors have at least two subtypes, which can be distinguished by using stereoselective isomers of these pharmacological medicines. SKF 10047 has nanomolar affinity to Sigma-1 (σ-1) site and has micromolar affinity to Sigma-2 (σ-2) site. Haloperidol has a similar affinity to both subtypes.

It was reported that some of Sigma ligands in combination with opioids or opiates are able to modulate their analgesic effect. It is known, for example, that haloperidol increases the activity of different opioids and opiates, such as morphine, DADL or bremazocine [Chichenkov, O. N. et al:Effect of haloperidol on the analgesic activity of intracisternally and given intrathecally as injected opiate agonists,Farmakologiya i Toksikologiya(Moscow) (1985), 48(4), 58-61]. Chien C. et al. also indicate the synergistic effect of the combination of haloperidol and morphine [Selective antagonism of opioid analgesia by sigma system,J. Pharmacol. Exp. Ther. (1994), 271, 1583-1590 and Sigma antagonists potentiate opioid analgesia in rats, Neurosci. Lett. (1995), 190, 137-139], and Marazzo A. et al. tied to the ability of Sigma ligand +)-MR200 modulate mediated by κ-opioid receptors in analgesia. Mei J., et al. confirmed the value of Sigma-1 receptors as modulating analgetic activity of opioid drugs [Sigma 1 receptor modulation of opioid analgesia in the mouse, J. Pharmacol. Exp. Ther.(2002), 300(3), 1070-1074]. However, in all these cases is the presence of dependence related problems caused by opioids and opiates.

One of the pharmacological approaches to solve the opioid and opiate dependence was co-administration of opioids or opiates and Sigma ligands. For example, agonist Sigma-1 receptors SA4503, as shown, has a modulating effect on addicted to morphine [Nomura, M., et al: Studies on drug dependence (Rept. 322): Attenuation of morphine - and psychostimulants-induced place preference by sigma 1 receptor agonist SA4503, 72ndAnnual Meeting of the Japanese Pharmacological Society (Sapporo, Japan-March 1999)]. Also, the agonist Sigma-1 DHEA showed some ability to attenuate the development of morphine dependence [Noda, Y., et al: A neuroactive steroid, dehydroepiandrosterone sulfate, attenuates the development of morphine dependence: an association with sigma 1 receptors, 31stAnnual Meeting of the Society of Neuroscience (San Diego-Nov 2001)]. In ER specified using Sigma-ligands for the treatment of narcotic addiction to morphine, cocaine and methamphetamine. However, neither one of these approaches does not show the increase of analgesic effect of morphine.

It is therefore desirable to find a Sigma-ligands synergistically to potentiate the analgesic effects opioideven opiates with the weakening at the same time based on them.

The INVENTION

Unexpectedly discovered that certain specific Sigma-ligands demonstrate ability synergistically to potentiate the analgesic effects of opioids or opiates, reducing at the same time caused by the dependency.

One of the objects of the present invention relates to the combination of at least one Sigma ligand and at least opioid or opiate compounds, and the Sigma ligand has General formula (I):

where

R1selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted, alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted geterotsiklicheskikh, -COR8, -C(O)OR8, -C(O)NR8R9,- (C=NR8, -CN, -OR8, -OC(O)R8, -S(O)t-R8, -NR8R9, -NR8C(O)R9, -NO2, -N=CR8R9or halogen;

R2selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted, alkenyl, substituted or n is substituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted geterotsiklicheskikh, -COR8, -C(O)OR8, -C(O)NR8R9,- (C=NR8, -CN, -OR8, -OC(O)R8, -S(O)t-R8, -NR8R9, -NR8C(O)R9, -NO2, -N=CR8R9or halogen;

R3andR4independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted, alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted geterotsiklicheskikh, -COR8, -C(O)OR8, -C(O)NR8R9,- (C=NR8, -CN, -OR8, -OC(O)R8, -S(O)t-R8, -NR8R9, -NR8C(O)R9, -NO2, -N=CR8R9or halogen, or together they form a condensed ring system;

R5andR6independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted, alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, and substituted and unsubstituted geterotsiklicheskikh, -COR8, -C(O)OR8, -C(O)NR8R9,- (C=NR8, -CN, -OR8, -OC(O)R8, -S(O)t-R8, -NR8R9, -NR8C(O)R9, -NO2, -N=CR8R9or halogen, or together they form with the nitrogen atom to which they are attached, a substituted or unsubstituted heterocyclic group;

nselected from 1, 2, 3, 4, 5, 6, 7 or 8;

tis 1, 2 or 3;

R8andR9each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted, alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkoxy, substituted or unsubstituted, aryloxy or halogen;

or its pharmaceutically acceptable salt, isomer, prodrug or MES.

Another object of this invention relates to the simultaneous, separate or sequential administration of combination, as defined above, to enhance the analgesic potency of the opioid or opiate and/or reduce dependence on them.

BRIEF DESCRIPTION of FIGURES

Figure 1: Effects of dose-response with the introduction of compound 63 in the acute experience (10, 20, 40 and 80 mg/kg/b) when the test otdergivanija tail on the male mice CD-1 DT (And) and CD-1 σ1R-KO (In). Compounds were administered 30 minutes before the test is. The data obtained in 12 (And) or 10 (In) animals in the group, are presented as arithmetic mean ± RMS delay otdergivanija tail (s). ***p<0,001 when compared with the group treated with the carrier (GMC 0,5%) (postdepression analysis on the criterion of multiple comparisons Newman-Kalsa).

Figure 2: Effects of dose-response with the introduction of morphine in acute experience (1,25, 2,5, 5 and 10 mg/kg, s/C) when the test otdergivanija tail on the male mice CD-1 DT. Compounds were administered 30 minutes before the test. Data obtained by the group of 8 animals presented as arithmetic mean ± RMS delay otdergivanija tail (s). *p<0,05, ***p<0,001 when compared with the group treated with the vehicle (saline) (postdepression analysis on the criterion of multiple comparisons Newman-Kalsa).

Figure 3: Effects of dose-response with the introduction of morphine in acute experience (1,25, 2,5, 5 and 10 mg/kg, s/C) when the test otdergivanija tail on the male mice CD-1 σ1R-KO. Compounds were administered 30 minutes before the test. Data received by the group from 10-11 animals presented as arithmetic mean ± RMS delay otdergivanija tail (s). ***p<0,001 when compared with the group treated with the vehicle (saline) (postdepression analysis on the criterion of multiple comparisons Newman-Kalsa).

Figure 4: Sigmoidal curves hung is on dose-response for morphine (1,25, 2.5, 5, and 10 mg/kg, s/C) when the test otdergivanija tail on the male mice CD-1 DT and σ1R-KO. Compounds were administered 30 minutes before the test. Data received by the group from 8-11 animals presented as arithmetic mean ± standard deviation of the percentage of analgesia (%). Insert: delay otdergivanija tail as DT and σ1R-KO in the group treated with the carrier. *p<0,05, ***p<0,001 when compared with the corresponding group treated with the vehicle (saline) (postdepression analysis on the criterion of multiple comparisons Newman-Kalsa).

Figure 5: (A)Strengthening the antinociceptive actions of morphine (2 mg/kg, s/C) compound 63 (10, 20, 40 mg/kg b/W) when tested in otdergivanija tail in male mice CD-1 DT. Compounds were administered 30 minutes before the test. Data obtained from groups of 11-12 animals presented as arithmetic mean ± RMS delay otdergivanija tail (s). ***p<0,001 when compared with the group treated with the carrier;###p<0,001 when compared with the group treated with morphine (2 mg/kg) (postdepression analysis on the criterion of multiple comparisons Newman-Kalsa).In)Image sigmoidal curves dose-response.

Figure 6: Sigmoidal curves dose-response for morphine (1, 2, 4 and 10 mg/kg, s/C) and the combination of compound 63 (40 mg/kg/b) with morphine (1, 2, and 4 mg/kg, s/C) when the test otdergivanija tail male m the necks CD-1 DT. Compounds were administered 30 minutes before the test. Data received by the group from 10-11 animals presented as arithmetic mean ± standard deviation of the percentage of analgesia (%). **p<0,01, ***p<0,001 when compared with the corresponding group treated with the carrier (postdepression analysis on the criterion of multiple comparisons Newman-Kalsa).#p<0,05 when compared with the corresponding group treated with morphine (2 and 4 mg/kg) (t-test to compare two independent samples).

Figure 7: Antinociceptive effects of morphine (MOR) and the combination of morphine + connection 63 with the test otdergivanija tail on the male mice CD-1 DT and σ1R-KO. Compounds were administered 30 minutes before the test. Doses of medicinal substances are expressed in mg/kg (parentheses on the chart). Data obtained from groups of 6-14 animals presented as arithmetic mean ± RMS delay otdergivanija tail (s). ***p<0,001 when compared with DT group treated with the carrier;###p<0,001 when compared with DT group treated with MOR + connection 63. (Postdepression analysis on the criterion of multiple comparisons Newman-Kalsa).

Figure 8: Enhanced synergistic effect of compound 63 and 11 when analgesia mediated by morphine when compared with the well-known Sigma-ligand BD1063.

Figure 9: Action connection 63 (25 mg/kg s/C) on a positive reinforce what their effects, created by morphine, when the paradigm of a conditioned reflex (estimated values).

Figure 10:Action connection63 (25 mg/kg s/C) positive reinforcing effects caused by morphine, when the paradigm of a conditioned reflex in place. The time spent in the paired branches of the drug during pre-production of the conditioned reflex and in phase trials.

DETAILED description of the INVENTION

The compounds of formula (I) can be obtained as described in our previous application WO2006021462.

The term "salt" is to be understood as any form of active compounds used in accordance with this invention, in which the specified connection is in the ionic form or is charged and is connected with the counterion (cation or anion) or is in solution. This definition also includes salts of Quaternary ammonium compounds and complexes of the active molecule with other molecules and ions, in particular complexes formed by ionic interactions. This definition includes, in particular, physiologically acceptable salts; this term should be understood as equivalent to the term "pharmacologically acceptable salt".

The term "pharmacologically acceptable salt" in the context of this invention means any salt, which physiologically portable (usually the lake is acause, that it is not toxic, in particular, because of the counterion) when used appropriately to treat, use or enjoyment of, in particular, in humans and/or mammals. These physiologically acceptable salts can be formed with cations or bases and, in the context of this invention means that they are salts formed with at least one compound used in this invention is usually acid (deprotonated) - in this form, as the anion, and at least one physiologically tolerable cation, preferably inorganic, particularly when used in humans and/or mammals. Salts with alkali and alkaline earth metals are particularly preferred, in particular, as well as educated ammonium cations (NH4+). Preferred salts are formed with one or two sodium ions, one or two ions of potassium, magnesium or calcium. These physiologically acceptable salts can also be formed with anions or acids and, in the context of this invention, it is understood that they are salts formed with at least one compound used in accordance with this invention is usually protonated, for example, by nitrogen in this form as the cation, and at least one physiologically eranosian anion, in particular, when used in humans and/or mammals. This definition, in particular, includes, in the context of this invention, the salts formed with physiologically tolerated acid, i.e. salts of specific active compounds with physiologically tolerated organic or inorganic acids - in particular, when used in humans and/or mammals. Examples of this type of salts are those formed with: hydrochloric acid, Hydrobromic acid, sulfuric acid, methanesulfonic acid, marvinol acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, almond acid, fumaric acid, lactic acid or citric acid.

The term "MES" in accordance with this invention should be understood as meaning any form of the active compounds according to this invention, in which the specified connection is connected non-covalent bond with another molecule (usually a polar solvent, including, in particular, the hydrates and the alcoholate, such, for example, methanolate.

Any compound that is a prodrug of compounds of formula I, is also within the scope of this invention. The term "prodrug" is used in its broadest sense and encompasses those derivatives that are converted in vivo the compounds of the present invention. Examples of prodrugs include, but are not limited to, derivatives and metabolites of the compounds of formula I, which include biohydrology molecules, such as biokerosene amides, biohydrology esters, biohydrology carbamates, biohydrology carbonates, biohydrology ureides and biokerosene phosphate analogues. Preferably, the prodrugs of compounds with carboxyl functional groups are lower alkalemia esters of carboxylic acids. Esters of carboxylic acids are usually formed by esterification of any of the carboxylic acid groups present in the molecule. Prodrugs can be usually obtained using well-known methods such as described Burger Medicinal Chemistry and Drug Discovery 6th ed. (Donald J. Abraham ed., 2001, Wiley) and “Design and Applications of Prodrugs” (H. Bundgaard ed., 1985, Harwood Academic Publishers).

In the preferred embodiment R1in the compounds of formula I selected from H, -COR8or substituted or unsubstituted alkyl. More preferably, when R1selected from H, methyl or acetyl. The preferred embodiment is that, when R1represents N.

In another preferred embodiment R2represents H or alkyl, more preferably methyl.

In yet another preferred embodiment of this invention R3and R 4are meta - and paraprotex phenyl group, and preferably, they are independently selected from halogen or substituted or unsubstituted alkyl.

In a particularly preferred embodiment of the present invention both, R3and R4together with the phenyl group to form a condensed ring system, more preferably, the system afternova rings.

Also preferred in the context of this invention are embodiments where n is selected from 2, 3, 4.

And finally, in another embodiment, preferably, when R5and R6together form a morpholine-4-ilen group.

In preferred embodiments, the present invention encompasses a combination of at least one opioid or opiate with at least one compound of formula I selected from:

[1] 4-{2-(1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazole-3-yloxy)ethyl}of the research,

[2] 2-[1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazole-3-yloxy]-N,N-diethylethanamine,

[3] 1-(3,4-dichlorophenyl)-5-methyl-3-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazole,

[4] 1-(3,4-dichlorophenyl)-5-methyl-3-[3-(pyrrolidin-1-yl)propoxy]-1H-pyrazole,

[5] 1-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazole-3-yloxy)ethyl}piperidine,

[6] 1-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazole-3-yloxy]ethyl}-1H-imidazole,

[7] 3-{1-[2-(1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazole-3-yloxy)ethyl]piperidine-4-yl}-3H-imidazo[4,5-b]pyridine,

[8] 1-{2-[1-(3,4-di is lorgeril)-5-methyl-1H-pyrazole-3-yloxy]ethyl}-4-methylpiperazine,

[9] ethyl-4-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazole-3-yloxy]ethyl}of piperidinecarboxylate,

[10] 1-(4-(2-(1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazole-3-yloxy)ethyl)piperazine-1-yl)ethanone,

[11] 4-{2-[1-(4-methoxyphenyl)-5-methyl-1H-pyrazole-3-yloxy]ethyl}of the research,

[12] 1-(4-methoxyphenyl)-5-methyl-3-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazole,

[13] 1-(4-methoxyphenyl)-5-methyl-3-[3-(pyrrolidin-1-yl)propoxy]-1H-pyrazole,

[14] 1-[2-(1-(4-methoxyphenyl)-5-methyl-1H-pyrazole-3-yloxy)ethyl]piperidine,

[15] 1-{2-[1-(4-methoxyphenyl)-5-methyl-1H-pyrazole-3-yloxy]ethyl}-1H-imidazole,

[16] 4-{2-[1-(3,4-dichlorophenyl)-5-phenyl-1H-pyrazole-3-yloxy]ethyl}of the research,

[17] 1-(3,4-dichlorophenyl)-5-phenyl-3-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazole,

[18] 1-(3,4-dichlorophenyl)-5-phenyl-3-[3-(pyrrolidin-1-yl)propoxy]-1H-pyrazole,

[19] 1-{2-[1-(3,4-dichlorophenyl)-5-phenyl-1H-pyrazole-3-yloxy]ethyl}piperidine,

[20] 1-{2-[1-(3,4-dichlorophenyl)-5-phenyl-1H-pyrazole-3-yloxy]ethyl}-1H-imidazole,

[21] 2-{2-[1-(3,4-dichlorophenyl)-5-phenyl-1H-pyrazole-3-yloxy]ethyl}-1,2,3,4-tetrahydroisoquinoline,

[22] 4-{4-[1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazole-3-yloxy]butyl}of the research,

[23] 1-(3,4-dichlorophenyl)-5-methyl-3-[4-(pyrrolidin-1-yl)butoxy]-1H-pyrazole,

[24] 1-{4-[1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazole-3-yloxy]butyl}piperidine,

[25] 1-{4-[1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazole-3-yloxy]butyl}-4-methylpiperazine,

[26] 1-{4-[1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazole-3-yloxy]butyl}-1H-them is asola,

[27] 4-[1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazole-3-yloxy]-N,N-diethylbutyl-1-amine,

[28] 1-{4-[1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazole-3-yloxy]butyl}-4-phenylpiperidine,

[29] 1-{4-[1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazole-3-yloxy]butyl}-6,7-dihydro-1H-indol-4(5H)-she

[30] 2-{4-[1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazole-3-yloxy]butyl}-1,2,3,4-tetrahydroisoquinoline,

[31] 4-{2-[1-(3,4-dichlorophenyl)-5-isopropyl-1H-pyrazole-3-yloxy]ethyl}of the research,

[32] 2-[1-(3,4-dichlorophenyl)-5-isopropyl-1H-pyrazole-3-yloxy]-N,N-diethylethanamine,

[33] 1-(3,4-dichlorophenyl)-5-isopropyl-3-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazole,

[34] 1-(3,4-dichlorophenyl)-5-isopropyl-3-[3-(pyrrolidin-1-yl)propoxy]-1H-pyrazole,

[35] 1-{2-[1-(3,4-dichlorophenyl)-5-isopropyl-1H-pyrazole-3-yloxy]ethyl}piperidine,

[36] 2-{2-[1-(3,4-dichlorophenyl)-5-isopropyl-1H-pyrazole-3-yloxy]ethyl}-1,2,3,4-tetrahydroisoquinoline,

[37] 4-{2-[1-(3,4-dichlorophenyl)-1H-pyrazole-3-yloxy]ethyl}of the research,

[38] 2-[1-(3,4-dichlorophenyl)-1H-pyrazole-3-yloxy]-N,N-diethylethanamine,

[39] 1-(3,4-dichlorophenyl)-3-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazole,

[40] 1-{2-[1-(3,4-dichlorophenyl)-1H-pyrazole-3-yloxy]ethyl}piperidine,

[41] 1-(3,4-dichlorophenyl)-3-[3-(pyrrolidin-1-yl)propoxy]-1H-pyrazole,

[42] 1-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazole-3-yloxy]ethyl}piperazine,

[43] 1-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazole-3-yloxy]ethyl}pyrrolidin-3-amine,

[44] 4-{2-[1-(3,4-dichlorophenyl)-4,5-dimethyl-1H-pyrazole-3-yloxy]et the l}of the research,

[45] 4-{2-[1-(3,4-dichlorophenyl)-4,5-dimethyl-1H-pyrazole-3-yloxy]ethyl}of the research,

[46] 2-[1-(3,4-dichlorophenyl)-4,5-dimethyl-1H-pyrazole-3-yloxy]-N,N-diethylethanamine,

[47] 1-(3,4-dichlorophenyl)-4,5-dimethyl-3-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazole,

[48] 1-(3,4-dichlorophenyl)-4,5-dimethyl-3-[3-(pyrrolidin-1-yl)propoxy]-1H-pyrazole,

[49] 1-{2-[1-(3,4-dichlorophenyl)-4,5-dimethyl-1H-pyrazole-3-yloxy]ethyl}piperidine,

[50] 4-{4-[1-(3,4-dichlorophenyl)-1H-pyrazole-3-yloxy]butyl}of the research,

[51] (2S,6R)-4-{4-[1-(3,4-dichlorophenyl)-1H-pyrazole-3-yloxy]butyl}-2,6-dimethylmorpholine,

[52] 1-{4-[1-(3,4-dichlorophenyl)-1H-pyrazole-3-yloxy]butyl}piperidine,

[53] 1-(3,4-dichlorophenyl)-3-[4-(pyrrolidin-1-yl)butoxy]-1H-pyrazole,

[55] 4-[1-(3,4-dichlorophenyl)-1H-pyrazole-3-yloxy]-N,N-diethylbutyl-1-amine,

[56] N-benzyl-4-[1-(3,4-dichlorophenyl)-1H-pyrazole-3-yloxy]-N-methylbutane-1-amine,

[57] 4-[1-(3,4-dichlorophenyl)-1H-pyrazole-3-yloxy]-N-(2-methoxyethyl)-N-methylbutane-1-amine,

[58] 4-{4-[1-(3,4-dichlorophenyl)-1H-pyrazole-3-yloxy]butyl}thiomorpholine,

[59] 1-[1-(3,4-dichlorophenyl)-5-methyl-3-(2-morpholinoethoxy)-1H-pyrazole-4-yl]ethanone,

[60] 1-{1-(3,4-dichlorophenyl)-5-methyl-3-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazole-4-yl}ethanone,

[61] 1-{1-(3,4-dichlorophenyl)-5-methyl-3-[2-(piperidine-1-yl)ethoxy]-1H-pyrazole-4-yl}ethanone,

[62] 1-{1-(3,4-dichlorophenyl)-3-[2-(diethylamino)ethoxy)-5-methyl-1H-pyrazole-4-yl}ethanone,

[63] 4-{2-[5-methyl-1-(naphthalene-2-yl)-1H-pyrazole-3-yloxy]ethyl}of the research,

[64 N,N-diethyl-2-[5-methyl-1-(naphthalene-2-yl)-1H-pyrazole-3-yloxy]ethanamine,

[65] 1-{2-[5-methyl-1-(naphthalene-2-yl)-1H-pyrazole-3-yloxy]ethyl}piperidine,

[66] 5-methyl-1-(naphthalene-2-yl)-3-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazole,

or their pharmaceutically acceptable salts, solvate or prodrugs.

Opioids and opiates are compounds that bind to opioid receptors. Compounds that bind to opioid receptors within the scope of the present invention include natural opiates, such as morphine, codeine and thebaine; semi-synthetic opiates, derivatives of natural opioids, such as hydromorphone, hydrocodone, oxycodone, Oxymorphone, desomorphine, diacetylmorphine, Nicomorphine, depropaniser, benzylmorphine and Ethylmorphine; fully synthetic opioids, such as fentanyl, pethidine, methadone, tramadol and propoksifen; and endogenous opioid peptides, produced naturally in the body, such as endorphins, enkephalins, dynorphin and endomorphin and their analogues. Preferably, the ligand for opioid receptors used in accordance with this invention, is morphine or its analogs.

The term "analog" in the context of this invention refers to any compound structurally derived from a compound that binds to an opioid receptor or homologous to him, and causes analgesic effect. Examples of analogues by this definition included the Ute analogues of morphine, described, for example, in ER or ER.

The preferred combination of this invention consists of a combination of 4-{2-[5-methyl-1-(naphthalene-2-yl)-1H-pyrazole-3-yloxy]ethyl}of the research and morphine.

The combination of this invention may be made in the dosage form for simultaneous, separate or sequential injection with at least a pharmaceutically acceptable carrier, additive, auxiliary substance or excipient. It is implied that the combination of two active compounds can be entered:

a) In the form of combination, which is part of the same drug drugs, two active compounds in this case are inserted always at the same time.

b) as a combination of two elements, each with one of the active substances, resulting in simultaneous, sequential or separate administration. In a particular embodiment of a Sigma-ligand is introduced regardless of the opioid or opiate (i.e. two elements), but at the same time. In another specific embodiment of a Sigma-ligand is administered first, and then the opioid or opiate is administered separately or sequentially. In yet another embodiment of opioid or opiate is administered first, and then introduce a Sigma-ligand, separately or sequentially, as indicated.

Each of these specific and different routes of administration gives the desired is to function effectively: synergistic enhancement of opioid or opiate analgesia and/or reduced dependence on these drugs.

AIDS or additives can be selected from carriers, fillers, substances basics, improving slip agents, fillers, solvents, diluents, dyes, improves the taste of substances, such as sugar, antioxidants and/or agglutinating substances. In the case of suppositories this may include waxes, or esters of fatty acids or preservatives, emulsifiers and/or carriers for parenteral administration. The choice of these auxiliary substances and/or additives, and the amount that you want to use, will depend on the use of pharmaceutical compositions.

The pharmaceutical combination in accordance with this invention can be adapted for any kind of introduction, it can be oral or parenteral, for example, through the lungs, nasal, rectal and/or intravenously. Therefore, dosage form in accordance with this invention can be adapted for local or systemic administration, in particular, cutaneous, subcutaneous, intramuscular, intra-articular, intraperitoneal, light, cheek, sublingual, nasal, percutaneous, vaginal, oral, or parenteral administration.

Suitable preparations for oral administration are tablets, pills, chewing gum, capsules, granules, drops ilizarova.

Suitable preparations for parenteral administration are solutions, suspensions, renewable (instant) dry preparations or injected agents.

The combination of this invention may be made in the form of a depot in dissolved form or in the form of plasters for percutaneous introduction.

Preparations on the skin include ointments, gels, creams, lotions, suspensions or emulsions.

The preferred form for rectal injection is a form of suppositories.

The combination of at least one opioid or opiate, and at least one of the compounds of General formula I suitable for use in the enhancement of analgesic effect of opioids or opiates and/or to reduce dependence on them. These combinations could be administered simultaneously, separately or sequentially.

The combination of the present invention showing how the effect of enhancement of analgesia induced by opioids or opiates, and reduce dependence on them, but could be used in any case to achieve one of these goals.

For example, with regard to the joint introduction of the compounds of formula I and opioid or opiate, it could be aimed at maximizing opioid or opiate analgesic effect. In this scenario, it is possible to get additional beneficial effect of maintaining the same himself the level of analgesia at lower doses of opioid or opiate.

In another embodiment of the use of this combination can be designed to directly reduce dependence on opioids or opiates or addiction to them.

In the preferred embodiment of this invention includes applying a combination of specified here as to enhance the analgesic effect of opioids or opiates, and to reduce at the same time dependence caused them.

The dosage that should be used in a patient depends on the patient's weight, species introduction, pathological conditions and disease severity. The preferred dosage regimen include the introduction of the compounds of formula (I) in the range from 0.5 to 100 mg/kg and opioid or opiate is from 0.15 to 15 mg/kg, and they are administered one or more times per day.

Another object of this invention is based on the discovery that Sigma ligands capable at the same time to the synergetic enhancement of analgesic effect of opioids and opiates and reduce dependence caused by them. This aspect of the present invention includes a combination of at least one Sigma ligand and at least opioid or opiate compounds. This combination is then injected simultaneously, separately or sequentially, to potentiate the analgesic effects of opioid or opiate, and to reduce dependence on them.

In another embodiment of this is subramania used opiate preferably is morphine or its equivalent.

The following examples will serve as illustration of the present invention.

Example 1: Synergistic effect of compound 63 with analgesia mediated by morphine

a)modulation of morphine analgesia test otdergivanija tail

Pain, caused by a combination of connection 63, the Sigma-1 ligand and morphine was assessed by the test of otdergivanija tail according to the method described by Carlsson et al. [Neurosci Lett. 1986 Nov 21; 71(3):356-60] in mice CD-1 wild-type (DT), and mice deficient in the Sigma-1 (KOS).

First, the efficiency of the connection only 63 were evaluated in mice DT, and by introducing different doses (10, 20, 40 and 80 mg/kg/b). Connection 63 had no significant effect on the response delay, except for the highest tested dose. As expected, this effect is not even present in mice TO (see figure 1).

In contrast, morphine caused a clear dose-dependent analgesic effect on mice as DT, and TO have similar effectiveness and value (AT 3.5 and 3.7 mg/kg for diesel fuel and KO, respectively), which indicates that a mouse TO normal receive analgesia morphine under these conditions, research on otdergivanija tail (see figures 2, 3 and 4).

Then the pain created by the combination of compounds 63 and morphine, were evaluated in mice DT. The figure 5 shows the increased antinociceptive dei is the conduct of morphine (2 mg/kg, p/C) connection 63, represented by delay otdergivanija tail (a) and by the percentage of analgesia (In).

As shown in figure 6, sigmoidal curves dose-response in mice CD1 DT in combination with morphine (1, 2, and 4 mg/kg, s/C) with compound 63 (40 mg/kg/b) compared with morphine (1, 2, 4 and 10 mg/kg, p/K) show a significant increase in the percentage of analgesia with a combination and a significant reduction AD combination (ED=1,33) compared to a single morphine (ID=3,21). The combination of morphine with 40 mg/kg of compound 63 increases the strength of pain relief one of morphine with a factor of 2.4.

Groups of mice received a single morphine (1 mg/kg) and in combination with compound 63 (40 mg/kg), and was detected only 10% of anesthesia one morphine (insignificant) and 55% pain relief with a combination. This synergistic effect, however, disappears when the combination is administered to the mouse Sigma-1 KO, as shown in figure 7.

b) Modulation of morphine analgesia when tested on a hot plate

To further investigate the effect of compound 63 on analgesia morphine, performed experiments on a hot plate (supraspinally integrated reaction), as described Janicki et al. [Pharmacol. Biochem. Behave, 1979 Apr; 10(4):623-6). Was to assess the effect of compound 63 on morphine analgesia: groups of mice received only morphine (2.5 mg/kg) and morphing combination with compound 63 (40 mg/kg). When tested on the hot plate was performed at 50°C, found 45% of analgesic activity when one morphine and 83% with the combination of morphine and compound 63. When it was performed at 55°C, the morphine gave 43% of analgesic activity, and the combination is 94%. Therefore, the connection 63 is able to potentiate analgesia with morphine and also when tested on a hot plate.

Example 2: Enhanced synergistic effect of compound 63 and 11 when the anesthesia, mediated by morphine, when compared with the well-known Sigma-ligand BD1063

Analgesic effect of two of the compounds of this invention (compound 63 and the connection 11) and BD1063, well-known Sigma-1 ligand in combination with morphine was evaluated in mice CD-1 wild-type (DT) using test otdergivanija tail, as in example 1. The connection 63 and 11, and BD1063 were administered a single dose of 40 mg/kg/W for 30 minutes before administration of morphine (1 mg/kg, p/K).

The results presented in figures 8 show that all combinations of Sigma ligand with morphine was given the increased analgesic effect of morphine, although this effect was more pronounced in the case of joint injections connection 63 and 11 of the present invention.

Example 3: the weakening of the dependence caused by morphine, when combined with the introduction of compound 63

The weakening effect of addiction to morphine using joint is 63 was tested using the model, the paradigm of the formation of the conditioned reflex in place. Paradigms of a conditioned reflex to the place is the behavioral model used in mice to assess the possible properties of a medicinal product to give positive reinforcement/disgust. According to this paradigm, the effects of positive reinforcement in drug associated with the physical characteristics of the environment and, thus, the mouse will prefer to spend more time in the environment associated with drug possessing properties of positive reinforcement. This model also allows you to detect disgust effects of the medicinal product, and in this case, the mouse will avoid to stay in the Department associated with the medication, with properties to disgust.

The aim was to clarify the effects of the introduction of the connections 63, when the paradigm of a conditioned reflex in place of a mouse and its ability to modify the properties of positive reinforcement of morphine in this paradigm. Tested two different doses of morphine and compound 63 was administered once at a dose calculated according to the data obtained previously in models of neuropathic pain (data not shown).

Used male mice CD-1 (Charles River, France)weighing 20-22 g at the beginning of the experiment. Mice identified by the label on the tail and the size of the attended individually in controlled laboratory conditions with temperature, supported on the damage of 21±1°C, humidity 55±10% and a controlled cycle lighting (the light is switched on at 08:00 PM; off lighting at 20:00 hours). All experiments were performed in a room with low noise. Mice were given in excess food and water at will, except for the time of behavioral testing. All experimental procedures and animal husbandry were conducted according to standard ethical guidelines (European Community for the care and use of laboratory animals and approved by the local ethics Committee.

If the test were the following experimental groups:

Group 1 (n=12): saline + saline

Group 2 (n=14): morphine (1.5 mg/kg, p/K) + saline

Group 3 (n=11): morphine (5 mg/kg, p/K) + saline

Group 4 (n=12): saline + compound 63 (25 mg/kg, p/K)

Group 5 (n=11): morphine (1.5 mg/kg, p/K) + compound 63 (25 mg/kg, p/K)

Group 6 (n=12): morphine (5 mg/kg, p/K) + compound 63 (25 mg/kg, p/K)

Properties of positive reinforcement morphine and the potential effect of positive reinforcement/ability to disgust compound 63 was assessed by use of the apparatus adapted to the paradigm of a conditioned reflex preferences. The apparatus consists of two main square offices to develop a conditioned reflex, separated triangular Central office. In EMA preliminary phase of a conditioned reflex each mouse was placed in the middle of the Central office, and she had free access to both compartments of the apparatus for producing a conditioned reflex for 18 minutes, and the time spent in each compartment was recorded. Effects of drugs were balanced between departments to apply unbiased methodology. Phase of a conditioned reflex to mice for 6 days did alternate injections of drugs (morphine and/or connection 63) or saline. Saline and compound 63 was administered 30 minutes before injection of morphine or saline. Mice were restricted to the relevant Department immediately after the injection of morphine or saline through the use of the guillotine doors, mating with the walls, for 20 minutes. Drugs were administered at 1, 3 and 5 day, and saline at 2, 4 and 6 day. Control animals received saline every day. Phase tests were conducted as the preliminary phase of the formation of conditioned reflex, i.e. free access to both compartments for 18 minutes, and the time spent in each compartment was recorded. The assessment was calculated for each mouse as the difference between the time spent after the production of the conditioned reflex, and the time spent to develop a conditioned reflex, in the doubles Department for trials of medicinal products. Data were expressed as raw values assessment of the belts (seconds) (figure 9) and the time held in the doubles Department for testing drugs during the phases of pre-production of reflex and test (seconds) (figure 10). Estimate values of time were compared using univariate analysis of variance (between objects) with the subsequent a posteriori multiple comparison Dunnet. The value of time spent in the doubles Department for testing drugs for each group of mice during the estimates in the preliminary development of reflex and after running out of reflex, were compared using two-sided paired t-student test.

The results shown in figures 9 and 10, given in the following conclusions:

- Morphine introduced in a dose of 5 mg/kg, caused by the effects of positive reinforcement, revealed preference is due. There were no effects when morphine was administered in the dose of 1.5 mg/kg of These effective and ineffective dose of morphine used to assess possible interactions with the connection 63.

Connection 63 (25 mg/kg) did not produced any effect on the location of a conditioned reflex in a separate application. This result suggests that the connection 63 does not give the effects of positive reinforcement or the aversion when used in this dose.

Connection 63 (25 mg/kg) attenuated the effects of positive reinforcement,caused by morphine, when the paradigm of a conditioned reflex in place. Thus, the connection 63 suppressed reactions positive reinforcement, called the effective dose of morphine (5 mg/kg) and were not given any due to the reaction when it was combined with an ineffective dose of morphine (1.5 mg/kg).

1. The combination with an analgesic effect for at least one Sigma ligand and at least one opioid or opiate compounds selected from morphine or its structural derivatives of fentanyl and tramadol, for simultaneous, separate or sequential administration, and the Sigma ligand has General formula (I)

where
R1selected from the group consisting of hydrogen and alkyl;
R2selected from the group consisting of hydrogen, alkyl and arylalkyl;
R3and R4independently selected from the group consisting of hydrogen, alkyl, arylalkyl, alkoxy and halogen, or together they form a condensed ring system;
R5and R6independently selected from the group consisting of hydrogen, alkyl, or together they form with the nitrogen atom to which they are attached, heterocyclic group;
n is selected from 1, 2, 3, 4, 5 or 6;
or its pharmaceutically acceptable salt, prodrug, selected from biogerontology amide, complex, ester, carbamate, carbonate and ureido, or MES, selected from a hydrate or alcoholate.

2. The combination according to claim 1, where R1selected from H and alkyl.

3. The combination according to claim 1, where R2denotes H or alkyl.

4. The combination according to claim 1, where R3and R4located in the meta - and para-positions of the phenyl group.

5. The combination according to claim 1, where R3and R4independently selected from halogen and alkyl.

6. The combination according to claim 1, where R3and R4together form a condensed naftalina ring system.

7. The combination according to claim 1, where n is selected from 2, 3, 4.

8. The combination according to claim 1, where R5and R6together form a morpholine-4-ilen group.

9. The combination according to claim 1, where the compound of formula I selected from:
[11] 4-{2-[1-(4-methoxyphenyl)-5-methyl-1H-pyrazole-3-yloxy]ethyl}of the research,
[63] 4-{2-[5-methyl-1-(naphthalene-2-yl)-1H-pyrazole-3-yloxy]ethyl}of the research,
or their pharmaceutically acceptable salts, MES, selected from a hydrate or alcoholate, or prodrug selected from biogerontology amide, complex, ester, carbamate, carbonate and ureido.

10. The combination according to claim 1, where the opiate selected from the group consisting of morphine, hydromorphone, Oxymorphone, desomorphine, diacetylmorphine, Nicomorphine, DIPROPYLENE, benzylmorphine, Ethylmorphine, fentanyl and tramadol.

11. The combination according to claim 1, which includes 4-{2-[1-(4-methoxyphenyl)-5-methyl-1H-pyrazole-3-yloxy]ethyl}morpholine and morphine.

12. The combination according to claim 1, which includes 4-{2-[5-methyl-1-(is aftalen-2-yl)-1H-pyrazole-3-yloxy]ethyl}morpholine and morphine.

13. The use of a combination according to any one of the preceding paragraphs to obtain drugs potentiating the analgesic effect of morphine or its structural derivatives of fentanyl or tramadol and/or to reduce the resulting dependencies.

14. Use item 13, where the drug potentiates the analgesic effect of morphine or its structural derivatives of fentanyl or tramadol.

15. Use item 13, where the drug reduces the dependence caused by morphine or its structural derivatives, fentanyl or tramadol.

16. Applying a combination of at least one Sigma ligand of General formula (I)defined in claim 1, and at least one opioid or opiate compounds for obtaining a medicinal product for simultaneous, separate or sequential administration, for potentiation of the analgesic effect of opioids or opiates, and to reduce the resulting dependence and opiate selected from the group consisting of morphine, hydromorphone, Oxymorphone, desomorphine, diacetylmorphine, Nicomorphine, DIPROPYLENE, benzylmorphine, Ethylmorphine, fentanyl and tramadol.



 

Same patents:

FIELD: biotechnologies.

SUBSTANCE: conjugate represents benzoate-hydrocodone that has the following structure: benzoate-hydrocodone (Bz-HC). Invention also pertains to the application of pharmaceutical compound for obtaining the drug for curing the patient with illness, disease or condition mediated by opioid binding to the opioid receptors of the patient.

EFFECT: improvement of medical treatment efficiency or prevention of drug abuse, drug withdrawal symptoms or pain relief.

10 cl, 11 ex, 4 tbl, 20 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to psychiatry and drug addiction, and may be used for detoxification-infusion therapy of the patients used psychotropic cannabis products. That is ensured by the infusion intravenous drop-by-drop sequential administration of drugs. A mixture containing 5% glucose 200 ml, 25% magnesium sulphate 10 ml and 4% potassium chloride 10 ml are administered. That is combined with the additional bolus administration of 5% vitamin B1 2 ml. That is followed by introducing a mixture containing 0.9% normal saline 200 ml and 20% piracetam 10 ml. That is added with the bolus administration of 5% vitamin B6 10 ml. Then, a mixture containing rheopolyglucin 200 ml, 5% ascorbic acid 5 ml and 1% nicotinic acid 1 ml is administered. Then, a mixture containing 0.9% normal saline 200 ml and 2.4% aminophylline 5 ml is administered. The procedure is performed twice a day for 10 days.

EFFECT: method provides the higher therapeutic effectiveness and reduced length of the therapy, as well as the presented method is reproducible easily.

1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and describes a disulphiram implant for treating the alcohol or opiate addictive patients. The implant contains disulphiram 95.0-59.0 wt %, nitrogen polymer composition 4.8-40.5 wt % and stearic acid or magnesium stearate 0.2-0.5 wt %. The nitrogen polymer composition contains N-vinylpyrrolidone and 2-methyl-5-vinylpyridine copolymer or salts of branched oligomers hexamethylene diamine and guanidine, and polyvinylpyrrolidone.

EFFECT: implant may be used in addictology and provides a prolonged and uniform release of disulphiram with improving incisional wound healing.

5 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are presented methods of treating or preventing an addiction or recurrent addictive behaviour, including: alcohol, nicotine, marijuana, marijuana derivative, opioid receptor antagonist, benzodiazepine, barbiturate and psychostimulant by administering the peroxisome proliferator-activated receptor gamma (PPARγ) agonist thiazolidinedione, alone or in a combination with another therapeutic agent - an opioid receptor agonist, a mixed partial opioid receptor agonist/antagonist, an anti-depressant, an antiepileptic agent, an antiemetic agent, a corticotrophin releasing factor 1 (CRF-1) receptor antagonist, a selective serotonin 5-HT3 receptor antagonist, a 5-HT2A/2C antagonist or a cannabinoid 1 (CB1) receptor antagonist (versions), related pharmaceutical compositions with the above combinations (versions), a standard dosage form (versions) and kits (versions).

EFFECT: it is shown that the PPARγ agonist pioglitazone had no effect on amphetamine sensitisation, however it reduced opiate consumption and opiate addiction, also reduced nicotine self-administration in rats, and reduced alcohol consumption if synergistically combined with topiramate Pioglitazone reduced ethanol self-administration in rats.

33 cl, 23 dwg, 27 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, particularly to pharmacology, and concerns the new application of 5-ethoxy-2-[2-(morpholino)ethylthio]-benzimidazole dihydrochloride (the anxiolytic Afobazole) as a medication for withdrawal syndrome management in opiate dependence. It is shown that Afobazole administered in a single or sub-chronic dose decreases the manifestations of 'spontaneous' or naloxone-caused morphine withdrawal syndrome, i.e. decreases physical morphine dependence.

EFFECT: anxiolytic Afobazole represents an effective medication for correcting the clinical manifestations of opiate withdrawal syndrome.

3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and represents a drug preparation containing 97.0-59.5 wt % of naltrexone base, 0.5-3.0 wt % of corticosteroid specified in triamcinolone, betamethasone or dexamethasone, 2.0-37.0 wt % of a nitrogen-containing polymer composition and 0.2-0.5 wt % of stearic acid or magnesium stearate. The nitrogen-containing polymer composition contains N-vinylpyrrolidone and 2-methyl-5-vinylpyridine copolymer or a salt of branched oligomers hexamethylene diamine and guanidine, and polyvinylpyrrolidone. The drug preparation may be used in addictology for treating the alcohol- or opioid-dependent patients.

EFFECT: invention provides prolonged and uniform naltrexone release with a lower probability of the implant rejection caused by an inflammatory response.

2 cl, 3 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine, namely to pharmaceutical industry and deals with disulfiram-based medication, which additionally contains corticosteroid. Medicine contains 59.5-97.0 wt % of disulfiram base, 0.5-3.0 wt % of corticosteroid, 2.0-37.0 wt % of nitrogen-containing polymer composition and 0.2-0.5 wt % of stearic acid or magnesium stearate. Composition of nitrogen-containing polymers includes copolymer of N-vinylpyrrolidone and 2-methyl-5-vinylpyridine or salts of dissolved oligomers of hexamethylenediamine and guanidine and polyvinylpyrrolidone.

EFFECT: medication can be applied in addictology for treatment of alcohol or opiate-dependent patient.

2 cl, 4 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine and represents a method for detoxification infusion therapy of drug-impaired patients involving the introduction of an infusion preparation and preparations enhancing the somatic state, differing by the fact that the therapy is prescribed once admitted to hospital and starts with measuring the extent of the infusion therapy by determining a degree of narcotisation manifestation, namely the presence of changed response syndrome, psychological dependence syndrome (obsession), physical dependence syndrome (compulsion) and withdrawal syndrome, body weight and daily physiological requirements that is followed by calculating the extent of the infusion therapy by formula: U=Kn×(Ks×MT)+PR; the infusion preparations are presented by electrolyte/glucose/colloid solutions in the ratio 3:3:1; it is added with psychopharmacotherapy; the therapeutic course makes 5-7 days in case of observing changed response, 10-14 days in case of psychological dependence, 15-21 days in case of physical dependence, 22-30 days in withdrawal syndrome with the extent of the infusion therapy calculated by formula is divided on 3 portions and administered in the patient at regular intervals within one day; if the patient is unassisted to compensate physiological requirements, the amount of parenteral solutions is reduced respectively.

EFFECT: invention provides adequate detoxification infusion therapy of patients in desomorphine consumption, higher effectiveness and reduced length of the therapy.

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted cyclohexylmethyl derivatives, having serotonin, noradrenaline or opioid receptor inhibiting activity, optionally in form of cis- or trans-diastereomers or mixture thereof in form of bases or salts with physiologically compatible acids. In formula (1): R2 denotes H or OH; R1 and R2 together denote or =N-OH, R3 denotes a phenyl residue which is unsubstituted or monosubstituted with a halogen atom or a heteroaryl residue selected from a five-member sulphur-containing heteroaryl such as a thienyl residue or an unsubstituted phenyl residue bonded through a C1-C4alkyl group, R4 and R5 independently denote an unsubstituted C1-C3alkyl or R4 and R5 together denote (CH2)3-6, R8 denotes a linear saturated C1-C4 alkyl group bonded with an aryl, which is unsubstituted or monosubstituted with halogen atoms, R9 denotes a saturated C1-C8alkyl; values of radicals R1, m, n, R6, R7, R10-R13 are given in the claim. The invention also relates to methods of producing compounds of formula (I), a medicinal agent containing said compounds, use of compounds of formula (I) to prepare a medicinal agent for anaesthetic treatment during sharp, neuropathic or chronic pain and for treating depression, urinary incontinence, diarrhoea and alcoholism.

EFFECT: high efficiency of using the compounds.

32 cl, 501 ex, 21 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical composition for pain management, as well as to application of said composition for making a drug for pain management. The declared composition contains a number of multilayer pills containing a water-soluble core, an antagonist layer containing HCI naltrexone and coating the core, an isolating polymer layer coating the antagonist layer, an agonist layer coating the isolating polymer layer, a delayed-release shell coating the agonist layer, an agent layer regulating osmotic pressure and containing sodium chloride immediately under the agonist layer. The isolating polymer layer contains acrylic-methacrylic ester polymers with quaternary ammonium groups, sodium lauryl sulphate in the amount of 1.6 wt % to 6.3 wt % and talc in the amount of 75 wt % to 125 wt % in relation to acrylic-methacrylic ester polymers with quaternary ammonium groups. The agonist layer contains morphine sulphate and hydroxypropyl cellulose, while sodium lauryl sulphate is found in the multilayer pills only in the isolating polymer layer.

EFFECT: invention provides preparing the pharmaceutical composition wherein the antagonist and agonist are isolated from each other, and the antagonist does not release from the composition due to osmotic pressure.

9 cl, 1 tbl, 23 dwg, 1 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to novel compound of formula (1) or its pharmaceutically acceptable salt, possessing SNS inhibiting properties. In general formula R1 represents (1) hydrogen atom, (2) halogen atom, (3) C1-6alkyl group or (4) C1-6halogenalkyl group (whereR1 can be present in any substitutable position of benzene or pyridine ring); L represents (1) simple bond, (2) -O- or (3) -CH2O- (where L can be present in position 5 or 6 of condensed cycle); R2 represents (1) C6-10aryl group (C6-10aryl group is optionally condensed with C3-6cycloalkane), optionally substituted with substituent(s), X represents carbon atom or nitrogen atom. Other values of radicals are given in the invention formula.

EFFECT: obtaining compounds which can be used to prepare medication for treatment or prevention of such diseases as neuropathic pain, nociceptive pain, dysuria, disseminated sclerosis, etc.

19 cl, 47 tbl, 237 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to compound of general formula (1), where A1 represents -N= or -CR7=, A2 represents -N= or -CR8, A3 represents -N= or -CR9=, A4 represents -N= or -CR10=; on condition that not more than one of residues A1, A2, A3 and A4 represents -N=; Y1, Y1′, Y2, Y2′, Y3, Y3′, Y4 and Y4' in each case independently on each other represent -H or -C1-8-alkyl; W represents -NR4-, where R4 represents -H or -C1-8-alkyl; R1, R2 and R3 independently on each other in each case represent R0, where R0 represents non-substituted or monosubstituted -C1-8-alkyl; non-substituted or monosubstituted -phenyl; non-substituted or monosubstituted - heteroaryl or non-substituted or monosubstituted -C1-8-alkylphenyl; or R1 and R2 together represent -(CH2)3-6-; R5, R5' R6, R6' R7 R8, R9, R10, R18 and R19 in each case independently on each other are selected from group, including -H, -F, -Cl, -Br, -I and -R0; where "heteroaryl" represents 5-membered cyclic aromatic residue, which contains 1 heteroatom, where heteroatom represents sulphur; where "alkyl" in each case represents branched or non-branched, saturated, non-substituted or monosubstituted aliphatic hydrocarbon residue; where with respect to residues "phenyl", "-C1-8-alkyl", "heteroaryl" and "-C1-8-alkylphenyl" "monosubstituted" means monosubstitution of one hydrogen atom with substituents, selected from group, including -F, -Cl, -Br, -I or -OH, in form of single stereoisomer or their mixture, free compound and/or its physiologically compatible salts.

EFFECT: obtained is novel compound and medication based on thereof, which can be applied in medicine for pain treatment.

9 cl, 15 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds possessing a high effectiveness in modulation of NMDA receptor activity.

EFFECT: compounds are applicable in treating the diseases and disorders, such as disturbed learning, cognitive activities, as well as for relieving and/or reducing neuropathic pain.

26 cl, 21 dwg, 2 tbl, 9 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to ligands in the form of synthetic peptide amides of a kappa-opiate receptor, and namely to agonists of the kappa-opiate receptor, which show a low inhibition degree of P450 CYP and a low degree of penetration into brain. According to the invention, synthetic peptide amide is described by the following formula:

EFFECT: pharmaceutical compositions containing the above compounds are suitable for prophylaxis and curing of pain and inflammation, which are related to different diseases and states.

19 cl, 11 dwg, 53 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and represents a pharmaceutical combination for treating in pain conditions in the form of a solid dosage form for oral administration, characterised by the fact that it contains Mirtazapine 5 mg - 50 mg; Tizanidine 0.5 - 6 mg in ratio 20:1-5:1, and a pharmaceutically acceptable carrier.

EFFECT: invention provides creating an effective agent for preventing or treating a pain condition well-tolerated by patients.

6 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: disclosed is use of a heptapeptide of general formula Tyr-D-Ala-Phe-Gly-Tyr-X-Ser-NH2, where X is D-Pro or Dh-Pro, or Dh-D-Pro, where Dh-Pro is 3,4-dehydroproline, as an antispasmodic, anxiolytic, central anti-inflammatory or anti-alcohol agent.

EFFECT: obtaining an agent used as an antispasmodic, anxiolytic, central anti-inflammatory or anti-alcohol agent.

3 cl, 8 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: invention relates to tevinol and orvinol derivatives of general formula I where R=OH; R1=H, CF3, C1-C4 alkyl, aryl, or (R+R1) stands for O=; R2=H, CH3; R3=H, CH3; R4=CH3, cyclopropylmethyl, allyl; Z~Z=CH2CH2, CH=CH. Invention also relates to method of obtaining formula I derivatives. Method lies in trifluoromethylation of respective aldehyde with formation of 21,21,21-trifluorotevinol, further oxidation of formed fluorine-containing alcohol with formation of respective ketone, which under influence of reagent, selected from the group, including R1Li, R1MgX, CF3Si(CH3)3, results in obtaining formula I tevinol derivatives. Orvinol derivatives are obtained by demethylation of tevinols.

EFFECT: formula I derivatives as ligands of opioid receptors with wide possibilities of varying their hydrophilic-hydrophobic balance.

9 cl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and represents a combination for the prevention, correction and therapy of pain related to neurodegeneration and/or associated with somatoform disorders, characterised by the fact that it consists of buspirone and doxepin taken in therapeutically effective amounts.

EFFECT: invention provides creating the combination providing the prolonged analgesic effect, including in persistent chronic pains.

5 cl, 2 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: invention relates to medicine, in particular, to surgery and can be applied for prolonged anesthetisation in early post operational period of patients with haemorrhoids of III-IV stage. For this purpose 1% solution of morphine in dose 0.1 ml per 10 kg of weight is introduced one time per day in peridural space between vertebras L2-L3 , or L3-L4 through catheter. Said quantity is diluted with 6 ml of physiological solution. Such volume of narcotic medicine ensures effective anesthetisation within 18-20 hours. After that, after said time expiry, 6.0 ml of 2% solution of lidocaine are additionally introduced, which ensures anesthetisation effect within 4 hours. Claimed procedure is repeated on 2 and 3 day in the same succession.

EFFECT: invention ensures prolonged anesthetisation in early post operational period within 3 days, due to reduction of introduced narcotic analgesic (morphine) dose, which makes it possible to reduce probability of development of addiction and development of side effects in patients.

3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to (hetero)arylcyclohexane derivatives of formula , where values of Y1, Y1', Y2, Y2', Y3, Y3', Y4, Y4', R1-R3 are given in the first claim, having affinity for the µ- opioid receptor and ORL 1-receptor.

EFFECT: enabling use of the derivatives in drugs for treating pain.

10 cl, 2 tbl, 40 ex

FIELD: veterinary medicine.

SUBSTANCE: against the background of lymphotropic injections of enzaprost F (prostaglandin F) and antibiotic in half-daily doses a course of lymph-stimulating injections is carried out in the subcutaneous tissue in the projection of the inguinal rings, which is administration into the interspinous ligament thickness of the spine at the level of L2-L6 of 1 ml per 5 kg of animal weight of mixture consisting of 32 IU lydase, 500 thousand IU roncoleukin, 0.1 ml butomidore, 4 ml of 2% lidocaine solution, and 5 ml of 40% glucose solution.

EFFECT: method enables to increase the effectiveness of therapy while reducing the probability of development of side effects and relapses of disease by increasing the drainage function of the lymphatic system, acceleration of lymph flow and processes of neogenesis while reducing the duration of treatment and reduction of daily doses.

1 tbl

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