Etomidate analogues with improved pharmacokinetic and pharmacodynamic properties

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to benzimidazole derivatives of general formula (I) and to their pharmaceutically acceptable salts, mixed stereoisomers and enantiomers, wherein R1 is L1C(O)OL2C(O)OT; R2 is unsubstituted C1-C10alkyl; L1 is a bond; L2 is unsubstituted C2-C10alkylene; T is C1-C10alkyl. Also, the invention refers to a pharmaceutical composition of the compound of formula (I) and a method of anaesthetising on the basis of using the compound of formula (I).

EFFECT: there are prepared new imidazole derivatives effective as an anaesthetising agent.

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Cross-reference to related application

For this application claims the priority, under 35 U. S. C. §119(e) on provisional application U.S. No. 61/040911, filed March 31, 2008, the full contents of which are incorporated herein by reference.

State support

The object of the present invention was made with support from the National institutes of health GM058448. The U.S. government has certain rights in relation to the present invention.

The technical field to which the invention relates

The present invention relates to analogs of etomidate that have improved pharmacokinetic and pharmacodynamic properties, and to their use as anaesthetics.

The level of technology

Every year in the USA only entered about 30 million General anaesthetics. At the concentrations required for maintenance of anesthesia, all General anesthetics provide potential significant and sometimes fatal side effects. Especially important is the suppression of cardiovascular and respiratory functions, which can be life-threatening, particularly the elderly, sick and injured patients. Such detrimental side effects caused almost all General anesthetics, and this explains why in General anesthetics have the smallest is terapevticheskii index (LD50/ED50) in comparison with any class of therapeutic drugs. Therefore, it is of great importance to develop safer anaesthetics with fewer side effects.

Etomidate (ethyl 3-(1-phenyl)imidazole-4-carboxylate) is a fast-acting sedative and hypnotic intravenous means on the basis of imidazole, which can be used for indexing and maintenance of General anesthesia or sedation with preserved consciousness. It exists as two enantiomers, however, (R)-enantiomer is 10 times more active as an anesthetic than (S)-enantiomer. It is (R)-enantiomer is used clinically (see Structure below 1). (R)-enantiomer induces the loss of the rectifying reflex tadpoles (Husain, S. S., and others, J Med Chem, 46:1257-1265 (2003)) and the loss of susceptibility in humans (Arden, J. R., and others, Anesthesiology, 65:19-27 (1986) when free water concentration of ~2 ám.

The structure of 1 - (R)-etomidate (ethyl 3-(1-phenyl)imidazole-4-carboxylate)

At the molecular level there is strong evidence that etomidate induces anaesthetic effect by strengthening the functions of GABAAndreceptors containing β2or β3subunit. Etomidate enhances GABA receptor-mediated currents induced by low concentrations of agonist, but minimally increases the currents induced by high concentrations of agonist. It shifts distorting the Yu dependence of the response on the concentration of the agonist to the left (lower value AS agonist). Etomidate also directly activates GABAAndreceptors in the absence of agonist.

Compared with other General anesthetics, etomidate has unusually high therapeutic index; therapeutic index (R)-etomidate for animals is 26.4 compared with 4.6 and 3.1 for thiopental and propofol, respectively (Janssen, P. A., Arzneimittelforschung, 21:1234- 1243 (1971), Glen, J. B., Br J Anaesth, 52:731-742 (1980), and Zhou, Anesth play mode display, 102:129- 134 (2006)). A relatively large latitude therapeutic range provided by etomidate, apparently, reflects its smaller impact on cardiovascular and respiratory function. Hemodynamic stability provided by etomidate at least partly due to the absence of depressants effect on sympathetic nerves and reflexes in the field of autonomic nervous system (Ebert, TJ., et al., Anesthesiology 76:725-733 (1992)). On the other hand, propofol, thiopental reduce sympathetic activity, dull reflexes in the field of autonomic nervous system and directly affect the contractility of the myocardium (Mazerolles, M., Fundam Clin Pharmacol, 10:298-303 (1996)). These actions lead to the suppression of cardiovascular and respiratory function even in healthy patients. Due to the smaller influence of (R)-etomidate on cardiovascular and respiratory function, he has become the preferred anesthetic for anesthesiologists, physicians-Rean is katalogow and emergency physicians for administration to patients, elderly or injured patients. However, the optimum with respect to this drug is reserved, and its use has been limited because of the potent and long-lasting inhibition of the synthesis of adrenocorticosteroids.

Inhibition of steroid synthesis is potentially fatal side effect of prolonged use of (R)-etomidate, especially for those patients who, otherwise, could greatly benefit from its favorable properties related to cardiovascular and respiratory functions: ill. This inhibition is extremely strong and occurs at much lower concentrations of (R)-etomidate, which are used to provide sedation or anesthesia. At the dose levels required for maintenance of General anesthesia, (R)-etomidate causes insufficiency of the adrenal cortex, which may persist for 4 days after cessation of prolonged infusion (Wagner, R. L., and White, P. F., Anesthesiology, 61:647-651 (1984)), resulting in a significant increase in mortality among patients who are in critical condition (Watt, L, and Ledingham, I. M., Anaesthesia, 39:973-981 (1984) and Ledingham, LM., and Watt, L, Lancet, 1:1270 (1983)). Apparently, mortality can be reduced experimentally by introducing exogenous steroids; however, this approach is not optimal, as dose the dose, the time and duration of treatment with steroids taken for each patient will be speculative. Moreover, the mere introduction of exogenous steroids can cause significant complications, including impaired glucose homeostasis and wound healing, immune suppression and fluid retention. Due to the deep influence of (R)-etomidate on the function of the adrenal cortex in its packaging has been added a special insert, warning about the dangers of prolonged infusion, and using (R)-etomidate for prolonged analgesia or anesthesia was discontinued.

The clinical significance of the suppression of the adrenal cortex after a single intravenous bolus is ambiguous. Cm. Morris, C, and McAllister, C, Anaesthesia, 60:737-740 (2005); Jackson, W. L., Jr., Chest, 127:1031-1038 (2005); Murray, H., Marik, P. E., Chest, 127:707-709 (2005); Zed, P. J., and others, Chem., 8:347-350 (2006); and Bloomfield, R., and Noble, D. W., Crit Care 10:161 (2006). Historically it is believed that suppression of adrenal function after a single bolus injection is short (<8 hours) and not clinically significant. However, this assumption is mainly based on a small amount of research patients undergoing planned operations that were not seriously ill. Cm. Wagner, R. L., and White, P. F., Anesthesiology, 61:647-651 (1984); Wagner, R. L., and others, N Engl J Med 310:1415-1421 (1984); Fragen, R. J., and others, Anesthesiology 61:652-656 (1984); and Duthie, D. J., and others, Br J Aaesth, 57:156-159 (1985). A number of recent studies and reports of severely ill patients demonstrates that even after a single bolus dose of (R)-etomidate suppression of the adrenal glands may persist for 24 hours or longer, and some believe that this increases the risk of death, especially when the occurrence of sepsis. Cm. Absalom A. and others, Anaesthesia, 54:861-867 (1999); Malerba, G. and others, Intensive Care Med, 31:388-392 (2005); den Brinker, M. and others, Intensive Care Med (2007); den Brinker, M., and others,/Clin Endocrinol Metab, 90:5110-5117 (2005); Lundy, J. B., and others,/Intensive Care Med, 22:111-117 (2007); Lipiner-Friedman, D. and others, Crit Care Med, 35:1012-1018 (2007); Vinclair, M. and others, Intensive Care Med., (2007); and Cotton, B. A., and others, Arch Surg, 143:62-67 (2008).

(R)-etomidate inhibits the synthesis of adrenocorticosteroids mainly due to the inhibition of 11β-hydroxylase, an important enzyme in the synthetic pathway leading to the obtaining of cortisol, corticosterone and aldosterone (see de Jong, F. H., and others,/Clin Endocrinol Metab, 59:1143-1147 (1984)). It was reported that premaxilla inhibitory concentration (R)-etomidate (IC50 of 0.5-30 nm (see Lamberts, S. W., and others, J Pharmacol Exp Ther, 240:259-264 (1987)), and the range of concentrations orders of magnitude lower than an anaesthetic concentration. If we consider the extremely high inhibitory activity is (R)-etomidate against 11β-hydroxylase along with its long-term (several hours) half-life (see Van Hamme, MJ. and others, Anesthesiology, 49:274-277 (1978)), we have assumed that the logical explanation of the giving goes beyond the explanation of the long time suppression of the adrenal cortex after administration of (R)-etomidate: in order after the introduction of the anaesthetic dose concentration of (R)-etomidate in serum decreased due to metabolism to a sufficient level at which the activity of 11β-hydroxylase is no longer inhibited, must go through many periods of half-life. This leads to the prediction that the period of suppression of the adrenal cortex can be reduced through the development of analogues (R)-etomidate, which rapidly undergo metabolism. You can also predict that such rapidly metabolized analogues can be extremely short periods of anesthetic action. This is another extremely desirable property of anesthetic, as it allows you to more accurately adjust the depth of anesthesia during surgery and quickly come out of anesthesia at the end of the operation.

There is a great need for more secure General anesthetics, in particular, for the application of the seriously ill. (R)-etomidate has many properties that make it an ideal General anesthetic, but its ability to suppress the synthesis of adrenocorticosteroids significantly limits its clinical applicability and safety.

As noted above, in engineering there is a need to develop analogues (R)-etomidate that will retain its useful properties (e.g., rapid onset of action, a small effect on blood pressure, high therapeutic index), but do not cause potentially dangerous the OE inhibition of adrenal cortex. Such analogues will allow you to more securely hold the anesthesia critically ill patients. The present invention meets this requirement.

The invention

The invention is directed to compounds of formula (I):

The compounds of formula (I) have improved pharmacokinetic and pharmacodynamic properties compared with (R)-etomidate that provides equivalent or improved anesthetic properties along with decreased undesirable side effects. The compounds of formula (I) are analogous to etomidate, while keeping the useful anesthetic properties of (R)-etomidate, but do not cause clinically significant inhibition of the adrenal cortex.

In the formula (I) R1is the L1C(O)OT or L1C(O)OL2C(O)OT. R2is substituted or unsubstituted C1-C10the alkyl, C2-C10alkenyl or C2-C10the quinil, or R1. Each R3independently is halogen or R2. n is an integer from 0 to 5. L1and L2each independently are a bond or substituted or unsubstituted C1-C10alkylene, C2-C10Alcanena or C2-C10albinyana. T is H, substituted or unsubstituted C1-C10the alkyl, C2-C10alkenyl or C2-C1 the quinil, NITROPHENOL or cyclopropyl. The compounds of formula (I) include pharmaceutically acceptable salts, mixtures of stereoisomers and enantiomers. The compounds of formula (I) are the object of the present invention, provided that if R1is the L1C(O)OT, R2is CH3, R3is fluorine, n is 1 and T is CH2CH3, L1is not a link.

Another aspect of the invention is directed to pharmaceutical anesthetic composition comprising an effective amount of the compounds of formula (I) and a pharmaceutically acceptable carrier.

Another aspect of the invention is directed to a method of providing anesthesia in a mammal, comprising the administration to a mammal an effective anesthetic compounds of formula (I) or pharmaceutical compositions.

Another aspect of the invention is the use of compounds of formula (I), mainly as described herein for the preparation of the dosage form, or in the production of dosage forms for maintenance of anesthesia in in need of the subject.

Brief description of drawings

Fig.1 is a graph showing the dependence of the response of anesthesia on the concentration of MOC-(R)-etomidate (measurement loss rectifier reflex; LORR) tadpoles. To construct this curve, the concentration-response were used in isolano 100 tadpoles. An anaesthetic IS was 8±2 μm. These results show that, MOC-(R)-etomidate is a potent General anesthetic. For comparison, AS (R)-etomidate is 2 μm (see Husain SS, etc. J Med Chem (2003).

In Fig.2 shows electrophysiological curves showing the amplification of currents mediated α1β2γ2LGABAAreceptors expressed in oocytesXenopusdue to MOC-(R)-etomidate and (R)-etomidate when their relative anesthetic concentrations. The first, third, and fifth curves are control. The second and fourth curves show similar effects gain 8 μm MOC-(R)-etomidate and 2 μm (R)-etomidate, respectively. These results show that, similarly to (R)-etomidate, MOC-(R)-etomidate increases submaximal GABAAreceptor currents induced by GABA.

In Fig.3 shows a graph of the dependence of the response on the concentration of GABA in the absence or in the presence of either 8 μm MOC-(R)-etomidate or 2 μm (R)-etomidate. These results show that as (R)-etomidate, MOC-(R)-etomidate shifts the curve for GABAAreceptors, showing the dependence of the response on the concentration of GABA, the left. Each point on the curve shows the value of measurements of three different oocytes. Index error represents the standard deviation.

In Fig.4 shows the percentage of Nemeth is alizirovannoj (R)-etomidate or nematerializiranih MOC-(R)-etomidate, as a function of the incubation time, incubation with the fraction of human liver S9 (+NADPH) at 37°C. For 40 minutes metabolism has been more than 99% of MOC-(R)-etomidate, while in this time interval (R)-etomidate not subjected to appreciable metabolism. These results show that the MOC-(R)-etomidate metabolized by liver enzymes, at least 100 times faster than the (R)-etomidate.

In Fig.5 shows electrophysiological curves showing no amplification of currents mediated α1β2γ2LGABAAreceptors expressed in oocytesXenopusunder the action of a carboxylic acid, a metabolite of MOC-(R)-etomidate. The first and last curves are the control (i.e. without metabolite). Second, third and fourth curves show the lack of effect of 10, 30 and 100 μm metabolite.

Fig.6 is a graph showing that (R)-etomidate inhibits the synthesis of cortisol adrenocortical H295R cells even at nanomolar concentrations (IC50=1,3±0,22 nm), whereas the metabolite MOC-(R)-etomidate has a relatively low inhibitory activity even at micromolar concentrations. Each point represents the average concentration of cortisol in 3 holes. Performance errors are standard deviations.

In Fig.7A shows the dependence of the response on the dose of anesthesia (as measured for LORR) to us for propofol, (R)-etomidate and MOC-(R)-etomidate. In Fig.7B shows that the duration of anesthesia increases almost linearly as the logarithm of the anaesthetic dose and that this duration is much shorter for MOC-(R)-etomidate compared with (R)-etomidate and propofol.

In Fig.8 shows the timing chart of blood pressure in rats after administration of equivalent anesthetic doses of propofol, (R)-etomidate and MOC-(R)-etomidate, and it is shown that the MOC-(R)-etomidate much less lowers blood pressure compared with propofol or (R)-etomidate. Each point shows the value within 30 seconds. Performance errors are standard deviations. The inset shows a typical curve of the arterial blood pressure before administration of the anesthetic.

In Fig.9 shows that the concentration of corticosterone in the plasma (adrenal cortical steroid) does not change in comparison with control (propylene glycol carrier) within 30 minutes after the introduction of MOC-(R)-etomidate, whereas after the introduction of the equivalent anaesthetic doses of (R)-etomidate it decreased significantly. Education in the rat corticosterone stimulated using ACTH1-24after 15 minutes after administration of anesthetic or media, and then after 15 minutes was measured concentration of corticosterone in the plasma. For the simple errors are standard deviations.

Detailed description of the invention

The present invention relates to safer analogues (R)-etomidate that preserve its useful characteristics (for example, a strong anesthetic properties, rapid onset of action, a small effect on blood pressure), but whose influence on the synthesis of adrenal cortical steroids and/or duration of anesthetic action is significantly reduced. Some options for implementation include analogs of etomidate (as R-and S-isomer), which is so rapidly metabolized to less active metabolite (e.g., metabolite, which is slightly inhibits 11β-hydroxylase, strengthens the function of the GABAAreceptors and/or provides anesthesia) that the suppression of the adrenal cortex and/or anesthetic action shall terminate immediately upon termination of the injection of anesthetic.

Compounds of the present invention can be represented as analogues atomdata (as R-and S-isomer), supplemented by one or more labile metabolized ester residues that are directly attached to different positions of molecule or via various linker groups (for example, -CH2CH2-). At the end of the ester residue can be "end group (for example, -CH3). Further disclosed are various options is the preferable implementation of the present invention.

The invention is directed to compounds of formula (I):

R1is the L1C(O)OT or L1C(O)OL2C(O)OT. In a preferred embodiment, R1is the L1C(O)OL2C(O)OT.

R2is substituted or unsubstituted C1-C10the alkyl, C2-C10alkenyl, or C2-C10the quinil, or R1. Preferably, R2is alkyl such as CH3or a complex ester of R1such as CH2CH2C(O)OCH3. In the most preferred embodiment, R2is CH3.

Each R3independently is halogen or R2. Preferred Halogens include fluorine and chlorine. The variable n is an integer from 0 to 5. In a preferred embodiment, n is in the range of 0-3, and most preferably is 0.

Linkers L1and L2each are independently a bond, substituted or unsubstituted C1-C10alkylamines, C2-C10alkanolamines or C2-C10alkynylamino group. The main chain of alkylene may contain one or more heteroatoms such as O, N or S. Preferably, each L1and L2independently is a bond or a linear C1-C4alkylamines group. Most preferably, L 1is a bond or CH2CH2and L2is CH2CH2CH2(CH2)4CH2or CH2CH2O(CH2)3. In the most preferred embodiment, L2is CH2CH2.

End group T can be H, substituted or unsubstituted C1-C10the alkyl, C2-C10alkenyl or C2-C10the quinil. The main chain of the alkyl may contain one or more heteroatoms such as O, N or S. end group can also be cyclopropyl, NITROPHENOL or any other electron-withdrawing group. Preferably, T is C1-C4alkyl group. Most preferably, T is CH3CH2CH3CH2CH2CH2CH3or CH2CH2OCH3. In the most preferred embodiment, T is CH3. In another most preferred embodiment, T is a NITROPHENOL.

The compound of formula (I) includes pharmaceutically acceptable salts, mixtures of stereoisomers and enantiomers. Compounds of the invention also include physiologically acceptable salts of the compounds of formula (I). Preferred physiologically acceptable salts are salts obtained by addition of acids known to the person skilled in the art. Traditional the ionic physiologically acceptable salts, obtained by adding acids include, but are not limited to, hydrochloride, oxalates and tartratami.

In a preferred embodiment, compounds, R1is the L1C(O)OL2C(O)OT, R2is CH3, n is 0, L1is a bond, L2is CH2CH2and T is CH3.

In another embodiment, compounds, R1is the L1C(O)OL2C(O)OT, R2is CH3, n is 0, L1is a bond, L2 is CH2(CH2)4CH2and T is CH2CH2CH2CH3.

In another embodiment, compounds, R1is the L1C(O)OL2C(O)OT, R2is CH3, n is 0, L1is a bond, L2is CH2CH2O(CH2)3and T is CH2CH2OCH3.

In some embodiments of compounds, R1is the L1C(O)OL2C(O)OT, R2is CH3each R3independently is halogen, n is 1-5, L1is a bond, L2is CH2CH2and T is CH3.

In other embodiments, connection, R1is the L1C(O)OL2C(O)OT, R2is CH3each R3is fluorine, n is 1-5, L1is a bond, L2is CH2CH2and T is CH3.

In still other embodiments, connection, R1is the tsya L 1C(O)OL2C(O)OT, R2is CH3each R3is fluorine, L1is a bond, L2is CH2CH2and T is CH3.

In other embodiments, connection, R1is the L1C(O)OT, R2is CH3at least one of R3is CH2CH2C(O)OCH3, L1is a bond and T is CH2CH3.

In the following embodiments, connection, R1is the L1C(O)OL2C(O)OT, R2is CH3at least one of R3is CH2CH2C(O)OCH3, L1is a bond, L2is CH2CH2and T is CH3.

In a preferred embodiment, compounds, R1is the L1C(O)OT, R2is CH2CH2C(O)OCH3, n is 0, L1is a bond and T is CH2CH3.

In another preferred embodiment, compounds, R1is the L1C(O)OT, R2is CH3, n is 0, L1is CH2CH2and T is CH2CH3.

Bridging carbon atom connecting the 6-membered ring and a 5-membered ring, is a chiral center. Therefore, the connection may be in the form of a pure enantiomer. In a preferred embodiment, the enantiomer is the R enantiomer.

Preferably, the compounds of formula (I) possess the same regardless of stereochemistry, as (R)-etomidate. R2, R3, L1, L2and T can be branched hydrocarbon chains, however, so that steric hindrance or the mate did not hinder the achievement of desired activity.

In some embodiments, the implementation, the compound includes two or more ester groups. Suitable group containing an ester (for example, linker - ester - terminal group or an ester - terminal group), can be entered on the bridge carbon or on different positions of the phenyl ring, or core molecule.

Preferred are quickly metabolized analogues of etomidate containing in the structure (R)-etomidate new ester residues, which steric not difficult, and/or whose electronic system isolated from the π-electron system imidazole and phenyl rings. It is believed that such ester residues, similar to those used in other medicines with ultra short duration, such as Remifentanil and esmolol, highly sensitive to hydrolysis by esterases. Cm. U.S. patent No. 3354173; U.S. patent No. 5466700; U.S. patent No. 5019583; and patent application U.S. No. US 2003/0055023.

The substituents R2, T, L1and L2each can be independently substituted one or more electron-withdrawing groups. In some vari is ntah implementation electron-withdrawing groups are halogen, NITROPHENOL or cyclopropyl. Can also be used by other electron-withdrawing groups, such as hydroxyl group, amino group, nitro group, nitrile group, sulphonate group, carboxylate group, a halogen group, mercaptopropyl and unsaturated alkyl groups. The presence of electron-withdrawing groups increases the partial positive charge on the carbonyl atom of ester, which increases the activity toward nucleophilic attack by esterases, and also increases the rate of hydrolysis by esterases.

Another aspect of the invention is directed to a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier.

Another aspect of the invention is directed to a method of providing anesthesia in a mammal, comprising the administration to a mammal the pharmaceutical composition substantially similar to that described above.

In some embodiments, the implementation, the method includes the introduction of an effective dose of the compound. Effective dose is from 0.01 to 100 mg/kg connection.

In a preferred embodiment, the method comprises the injection of a single effective dose of the compounds then may follow or may not follow a continuous infusion of soy is inane.

In some embodiments, the implementation, the method includes the introduction of a continuous infusion of an effective dose of the compounds of formula (I).

In some embodiments, the implementation, the method also includes an introduction to the mammal an effective amount of a therapeutic agent selected from other sedative hypnotic, analgesic money and muscle relaxant. Non-limiting examples of sedative hypnotic agents include benzodiazepines, barbiturates, ketamine, propofol, isoflurane and desflurane. Non-limiting examples of analgesic funds include non-steroidal anti-inflammatory drugs (NSAID), paracetamol/acetaminophen, inhibitors SOH-2 and opiates. Non-limiting examples of muscle relaxants include rapacuronium, miwakuriyu, succinylcholine, vecuronium and cisatracurium.

Compounds of the invention showed anesthetic activity and enhanced the activity of GABAAndthe receptors. Concentrations investigated in the analysis ofin vitrowere in the range from 4,32×10-5to 3.39×10-8g/ml and from 0.01 to 0.02 g/kg for analysesin vivo. Compounds of the invention showed a strong anesthetic and GABAAndreceptor effectsin vitroandin vivo. These results show that the compounds of the invention are highly active agents with potentin vitroandin vivoeffects it is Important to note, what compounds have reduced inhibitory activity against synthesis adrenocorticosteroidsin vitroandin vivoand/or short duration of anesthetic action.

The above compounds may be introduced alone or as mixtures with other connection, or in combination with acceptable pharmaceutical carriers. Thus, the invention also relates to pharmaceutical compositions that contain an effective amount of at least one compound of the invention with a pharmaceutically or physiologically acceptable carrier with or without him. If necessary, the compound may be introduced in the form of physiologically acceptable salts, such as salts obtained by addition of acid.

The invention also includes a method of treating animals or humans. This method includes the introduction of an animal or human an effective amount of at least one of the compounds of the invention, or a physiologically acceptable salt with a pharmaceutically acceptable carrier or without him. It is preferable to intravenous administration. Cm. U.S. patent No. 4289783, the full content of which is incorporated by reference.

The invention is a sedative sedative, which is rapidly metabolized and can be used to achieve and/or pederzani the anesthesia, sedation or otherwise decrease the sensitivity of the Central nervous system. Compared with alternative agents it has one or more of the following useful properties: the higher the activity, the smaller the duration of therapeutic action, shorter duration of action, side effects, reduced adrenocortical suppression, higher therapeutic index, lower toxicity, reduced suppression of the cardiovascular system and more easy selection of the desired effect. The invention can be introduced by a single intravenous bolus injection or continuous intravenous drip infusion. Other delivery methods may include oral, rectal, transmucosal, subcutaneous or inhalation.

Compounds of the invention can be obtained using the methods described in U.S. patent No. 3354173, the full content of which is incorporated by reference. Can be applied with appropriate modification of the starting compounds using well known methods in the art. Also compounds of the invention can be obtained according to the General synthetic procedure, which can be described as follows. First hydrolyzes the ester bond of etomidate or analog etomidate, giving imidazol-5-carbon is a new acid. Further, the carboxylic acid is condensed with a suitable group containing an ester (for example, linker - ester - terminal group). The condensation can be carried out using carbodiimide method or using other methods known in the art. It is preferable to start the synthesis from (R)-etomidate or similar fixed stereochemistry.

The following examples illustrate the General synthetic procedure, and specific obtaining the compounds of the present invention. The following examples show the formation of compounds of the present invention. Examples are explanatory and are not intended to in any way limit the invention described in the claims

EXAMPLES

Example 1

Synthesis of (R)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid (1)

A solution of R-ethyl-1-(1-phenylethyl)-1N-imidazole-5-carboxylate. HCl (R-etomidate.HCl), (281 mg, 1 mmol) in methanol (5 ml) and 10% aqueous NaOH (1.7 ml) was boiled under reflux for 30 minutes. After cooling, the solution was neutralized to 12.1 M HCl (0,351 ml). The mixture was dried using a rotary evaporator, the residue is suspended in the system methanol-dichloromethane 1:4 v/v, and sodium chloride was filtered. 1-(1-phenylethyl)-1N-imidazole-5-carboxylic acid1got the BL is using chromatography on a column of silica gel, balanced system methanol-dichloromethane 1:4 v/v.1H NMR spectrum: (CD3OD) δ of 9.30(d, 1H, imidazole CH), 8,23 (d, 1H, imidazole CH), 7,37 (m, 5H, phenyl), 6,64 (kV, 1H, Metin), of 1.97 (d, 3H, methyl). Cm. Scheme 1.

Scheme 1

Example 2

Synthesis of Methyl-3-hydroxypropionate (2)

The connection was received, as described by Bartlett and Rylander (see Bartlett, P. D., And Rylander, P. N., J. Amer. Chem. Soc, 73: 4273-4274 (1951), whose full content is included by reference). β-Propiolactone (4,36 g of 60.5 mmol) was added dropwise to a stirred solution of sodium methoxide (121 mg, 2,24 mmol) in anhydrous methanol (15 ml) at - 78°C. the Mixture was neutralized by adding an equivalent amount of HCl (2,24 ml 1M HCl). The mixture was filtered, evaporated on a rotary evaporator to remove the methanol, and the oily residue was distilled under reduced pressure, obtaining methyl-3-hydroxypropionate2(2.7 g, 43%).1H NMR spectrum (CDCl3) δ 3,88 (t, 2H, methylene), to 3.73 (s, 3H, methyl), 2,59 (d, 2H, methylene).

Example 3

Synthesis of (R)-3-Methoxy-3-oksipropil-1-(1-phenylethyl)-1H-imidazole-5-carboxylate (MOC-(R)-Etomidate, 3)

To a mixture of (R)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid1(1 mmol) and methyl-3-hydroxypropionate (115 mg, 1.1 mmol) in anhydrous dichloromethane (3.5 ml) was added dicyclohexylcarbodiimide (139 mg, 1.1 mmol) and p-dimethylaminopyridine (134 mg, 1.1 mmol). The solution was stirred at room themes is the temperature value within 48 hours. The precipitate was filtered, and the clear solution was applied on a column of silica gel, equilibrated with dichloromethane. Elution with 10% ether in dibromoethane gave the product which was further purified using preparative thin-layer chromatography in the system hexane-ethyl acetate 1:1 v/v for 1 mm thickness silicagel plate. The oily product was treated with HCl in anhydrous ethyl acetate, getting a white crystalline 3-methoxy-3-oksipropil-1-(1-phenylethyl)-1H-imidazole-5-carboxylate. HCl (MOC-(R)-etomidate. Hydrochloride) (200 mg, 59 %).1H NMR spectrum (CDCl3) δ of 8.92 (d, 1H, imidazole CH), 7,76 (d, 1H, imidazole CH), was 7.36 (m, 5H, phenyl), of 6.49 (q, 1H, Metin), 4,60 (m, 2H, methylene), to 3.73 (s, 3H, methyl), was 2.76 (t, 2H, methylene) a 2.01 (d, 3H, methyl).

Example 4

MOC-(R)-etomidate is a potent General anesthetic for tadpoles

For studies of anaesthetic activity used the test for loss rectifier reflex tadpoles. Group 5 tadpolesXenopus laevisin early stages of embryo limb was placed in 100 ml of oxygen-rich aqueous buffer solution of 2.5 mm buffer Tris HCl (pH=7) containing a concentration of MOC-(R)-etomidate in the range of 0.1 to 128 μm. For the structure of MOC-(R)-etomidate see Diagram 1.

Tadpoles manually turned every 5 minutes dropper processed on the flame. Assume that th is bastaki was under the influence of anesthesia, if they couldn't straighten up for 5 seconds. At all concentrations, the loss of response to the rectifier reflex stabilized within 30 minutes after exposure to MOS(R)-etomidate. No data on toxicity were observed; all exposed anesthesia tadpoles recovered their rectifier reflexes when returning to fresh water, rich in oxygen.

In Fig.1 shows the dependence of the response on the concentration of anaesthetic.

The proportion of tadpoles exposed to anesthesia, in each group increased with increasing concentrations of MOC-(R)-etomidate, and at the highest concentrations of MOC-(R)-etomidate (48-128 μm), all tadpoles were under the influence of anesthesia. Based on these data, an anaesthetic IS MOC-(R)-etomidate (i.e. the concentration at which 50% of the tadpoles was under anesthesia) was defined as 8±2 μm.

Example 5

MOC-(R)-Etomidate significantly strengthens the function of the GABAAndreceptor

MOC-(R)-Etomidate designed to induce anesthesia due to the molecular mechanism analogous to (R)-etomidate: by strengthening the functions of GABAAndthe receptor. GABAAndthe receptors of man, consisting of α1β2γ2Lsubunits expressed inXenopus laevisthe oocytes and was used to compare the effects of MOC-(R)-etomidate and (R-etomidate on GABA Andreceptor-mediated currents using dvukhmasshtabnogo method of fixing voltage. This combination of subunits was chosen due to the fact that it forms the most common subtype of GABAAndreceptor in the brain, and it is known that it is sensitive to etomidate.

Each oocyte was determined the concentration of GABA, which induces response to a current whose maximum amplitude is 5-10% of that which is induced due to 1 mm GABA (GABA concentration saturation of the receptor). This submaximal concentration is called EU5-10the concentration of GABA. To evaluate and compare the effects of MOC-(R)-etomidate and (R)-etomidate on GABA-ergicheskie currents were measured reference current, induced EC5-10GABA in pure form. After a 5 minute recovery period was measured test peak current, affecting the oocyte anesthetic for 90 seconds and then as an anesthetic, and the EU5-10GABA within 90 seconds. After the next 5 minute recovery period was repeated a control experiment to assess reversibility. In Fig.2 shows a typical control curves and analyses obtained in the absence and in the presence of the usual means, respectively, for the same oocyte. It was found that when anaesthetic IS (i.e., 8 is km) MOS(R)-etomidate increases the amplitude of the currents, called GABA, 450±130% (n=6 oocytes). These results are similar to the gain induced (R)-etomidate (660±240%) in anaesthetic EU50(i.e., 2 microns) for the same set of oocytes. Direct activation was also observed for small currents caused as MOS(R)-etomidate and (R)-etomidate, even before application of GABA.

Next, we studied the ability of MOC-(R)-etomidate and (R)-etomidate to shift the curve of dependence of the response on the concentration of GABA to the left (see Fig.3). In these experiments, the peak current response obtained at each concentration of GABA was normalized to the maximum response induced by 1 mm GABA. When anesthetic AS concentrations MOC-(R)-etomidate and (R)-etomidate amplified currents induced by low concentrations of GABA, but have a relatively small effect on the currents caused by high concentrations of GABA. This moved the curves of the response depends on the concentration of GABA to the left, reducing GABA IS (i.e., the concentration of GABA, which caused 50% of maximum response) from 12.7±0.4 µm in the absence of anesthetic to 3.3±0.1 ám in the presence of MOC-(R)-etomidate and 1.6±0.1 in the presence of (R)-etomidate, respectively. The hill coefficient was in the range of 1.5-1.8.

Example 6

In vitrometabolism of MOC-(R)-etomidate >100 faster than (R)-etomidate

Metabolic ratein vitro(combined fractions of the liver che is oweka S9) MOS(R)-etomidate compared with the speed of the metabolism of (R)-etomidate. Fraction of human liver S9 was chosen due to the fact that it is rich in a wide variety of enzymes, metabolizers drugs (including esterase), and it is traditionally used in the analyses of the stability of drugs in relation to metabolism. Since it is likely that the liver will be the body responsible for the metabolism of MOC-(R)-etomidatein vivoit also represents a source of enzymes for studies of metabolismin vitro.

10 μm of MOC-(R)-etomidate or (R)-etomidate incubated at 37°C With 0.3 mg/ml of the combined fraction of human liver S9, containing 1 mm NADPH. At various time points (0, 5, 10, 20 and 40 minutes) selected 100 ál aliquots of the reaction mixture, and their metabolism was stopped by adding 200 μl of acetonitrile. The aliquot was centrifuged and the concentration (nematerializiranih) usual means in the supernatant was measured quantitatively using HPLC with mass spectrometric detection.

Fig.4 is a semi-log graph of the dependence of the percentage nematerializiranih remaining anesthetic as a function of time of incubation in the fraction of human liver S9. Even after 40 minutes detected nematerializiranih (R)-etomidate, showing that its metabolic half-life of much more than 40 minutes. Completely different MOC-(R)-etomidate if the tro was subjected to metabolism in the fraction of human liver S9. The concentration of MOC-(R)-etomidate decreased as a first order process, achieving <1% of the initial concentration (i.e., <0.1 µm) for 40 minutes. The metabolic half-life of MOC-(R)-etomidate was calculated as 4.2 minutes. In these studies as an external standard was used buspirone to confirm the metabolic activity of the fractions of the liver. Its metabolic half-life was 15.4 minutes.

The structure of the metabolite formed after 40 minutes of incubation in the combined fraction of human liver S9 (+ nikotinamidadenindinukleotida), were analyzed using high-performance liquid chromatography/tandem mass spectrometry. Ion chromatogram registered the presence of only one metabolite. He had a molecular weight of 288, which corresponds to the carboxylic acid formed by hydrolysis of the remote ester residue of MOC-(R)-etomidate. Based on these results, we concluded that the rapid metabolism of MOC-(R)-etomidate occurred solely due to the proposed route, shown in Scheme 2, in which the remote ester residue of MOC-(R)-etomidate hydrolyzed, giving appropriate equivalent of carboxylic acid along with methanol as the leaving group.

Scheme 2

Example 7

Metabolite of MOC-(R)-atomi the ATA has a small or does not have anesthetic effects

Metabolite of MOC-(R)-etomidate (i.e., MOC-(R)-etomidate carboxylic acid) was obtained by hydrolysis of MOC-(R)-etomidate in phosphate buffer solution containing ~ 1 unit/ml esterase pig liver. During hydrolysis the pH was maintained at 8.4 per by adding NaOH. Then the reaction product was purified on TLC plate. NMR spectroscopy confirmed >99% of MOC-(R)-etomidate was subjected to hydrolysis to the expected carboxylic acid metabolite.

The metabolite was investigated on anesthetic activity using test loss rectifier reflex tadpoles. In this test 5 tadpoles were placed in 20 ml beakers containing metabolite at a concentration of 1000 μm. Even after 60 minutes no loss rectifier reflex tadpoles were observed, indicating that the metabolite does not have a significant anaesthetic activity.

Example 8

Metabolite of MOC-(R)-etomidate has a low or has no effect on the function of GMCAAndreceptor

The increased activity of GABAAndreceptor metabolite of MOC-(R)-etomidate was estimated using dvukhmasshtabnogo method of fixing voltage. In Fig.5 shows that even at concentrations up to 100 μm metabolite of MOC-(R)-etomidate has no significant effect on GABAAndreceptor-mediated currents.

Example 9

M is tablet MOC-(R)-etomidate has a low or has no effect on the synthesis of steroids in vitro

The ability of inhibition of steroid synthesisin vitrometabolite of MOC-(R)-etomidate was estimated using adrenocortical cell line human H295R (NCI - H295R; ATCC #CRL-2128). H295R cells expressed most of the key enzymes required for the biosynthesis of steroid hormones, including all the enzymes required for the biosynthesis of cortisol (e.g., 11β-hydroxylase). When stimulating Forskolin these cells produce cortisol and secrete it into the environment where it can be easily measured. Inhibition of 11β-hydroxylase blocks the synthesis of cortisol, reducing the concentration of cortisol in the analyzed environment.

H295R cells were grown until almost confluently in the culture medium (DMEM/F12, supplemented with 1% ITS, containing insulin, transferrin, selenium, linoleic acid, 2,5% NuSerum and Pen/Strep). The culture medium was placed in the analyzed environment, which provides a synthesis of cortisol (DMEM/F12, supplemented with 1% ITS, and 20 μm of Forskolin) together with either (R)-etomidate, or MOC-(R)-etomidate, or their metabolites (or no control). After 48 hours the synthesis of cortisol caused by Forskolin, 1.2 ml of the analyzed medium was collected, centrifuged to remove cells and debris) and the concentration of cortisol in the supernatant was measured using enzyme immunoassay.

In Fig.6 shows a comparison of ing berousek actions (R)-etomidate and metabolite MOC-(R)-etomidate on the synthesis of cortisol by H295R cells. The concentration of (R)-etomidate necessary to reduce the concentration of cortisol in the analyzed environment by 50% (i.e., IC50), was 1.3±0.2 nm, while the concentration of the metabolite of MOC-(R)-etomidate was at least 1000 times more, because even at a concentration of 1 μm was not observed a decrease in the concentration of cortisol in the analyzed environment by 50%. These results showed that the metabolite of MOC-(R)-etomidate has no inhibitory effect on the synthesis of cortisol by H295R cells.

Example 10

MOC-(R)-etomidate is a potent General anesthetic with ultrashort duration in rats

Within a short period of time the rats were kept in an acrylic chamber with a diameter of 3 inches and a length of 9 inches with the outlet at the end. The required dose of anesthetic was injected through the catheter into the lateral tail vein, with subsequent washing of approximately 1 ml isotonic. Immediately after injection, rats were removed from the constraining device and turned back. It is believed that in rats there is a loss of rectifying reflex, if they fail to turn over (on all four legs) within 5 seconds after doing drugs. To measure the duration of the loss of the rectifying reflex, which is defined as the time from drug administration until the moment when the animal inde is the super flips, we used the stopwatch. ED50 loss rectifier reflex when bolus introduction of anesthetic was determined on the basis of an anesthetic dose-dependent effect of loss rectifier reflex.

In Fig.7 shows the dependence of the response on the concentration of propofol, etomidate and MOC-(R)-etomidate loss rectifier reflex in rats. The number of rats, which saw a loss of rectifying reflex, increased with increasing the dose of anesthetic. At higher dose levels, all rats were under anesthesia, and explicit anaesthetic toxicity was not observed. From these data it follows that the ED50 values for loss rectifier reflex observed after bolus etomidate, propofol and MOC-(R)-etomidate were identified as 1,00±0,03 mg/kg (n=18), 4,1±0,3 mg/kg (n=20) and 5.2±1 mg/kg (n=20), respectively. At dose levels sufficient to induce loss of rectifying reflex in rats, all three anesthetic induced loss rectifier reflex within a few seconds after intravenous bolus injection. The duration of loss of rectifying reflex (measured as the time required for the rats to come to consciousness and to turn on all four paws) increased almost linearly on the logarithm of the dose of anesthetic (Fig.7B); however, the slope of this depending is, that depends on half-life in the brain, for the MOC-(R)-etomidate was an order of magnitude smaller (2,8±0,4) than for etomidate (27±7) or propofol (22±4). The tangents of the angle of inclination for etomidate and propofol were slightly different from each other. From the obtained data it is evident that at equivalent anesthetic doses, duration of loss of rectifying reflex ~10 times shorter for the MOC-(R)-etomidate than propofol or (R)-etomidate.

Example 13

MOC-(R)-etomidate has better hemodynamic stability compared with propofol and (R)-etomidate

Often etomidate prefer other agents to provide anesthesia in critically ill patients, as it better preserveshemodynamic stability. To determine whether the MOC-(R)-etomidate similarly to maintain hemodynamic stability, we measured and compared the effects of propofol, etomidate and MOC-(R)-etomidate and media (35% v/v propylene glycol in water) on heart rate and blood pressure in rats. For comparison, data of drugs at equivalent anesthetic level doses, each tool was administered intravenously at double the concentration of the ED50loss rectifier reflex (i.e., 2 mg/kg etomidate, 10 mg/kg of MOC-(R)-etomidate and 8 mg/kg of propofol). Volume of added propylene glycol was equally the output for groups of media etomidate and MOC-(R)-etomidate. After adaptation of animals data were recorded for 5 minutes before (baseline) and within 15 minutes after administration of the drug/carrier (Fig.8). Rats in each group had similar mean values of heart rate and blood pressure baseline within the first 5 minutes (391±49 beats per minute (BPM), 118±9 mm RT.cent.). The media did not cause significant changes of the average values of blood pressure compared to baseline (5±11 mm RT.art., n=3, at 90 seconds); for simplicity in Fig.9 data not shown. However, MOC-(R)-etomidate, etomidate and propofol (n=3 animals for each), each caused a significant reduction in average blood pressure compared to baseline and to each other in the row as the maximum value (-11±15 mm RT.art., -36±11 mm RT.article and -51±19 mm RT.cent.), and the duration significant effect (30 seconds 6.5 minutes and 7 minutes, respectively). Soon after injection for all groups, the media (36±14 BPM), MOS(R)-etomidate (24±33 BPM), etomidate (49±67 BPM) and propofol (64±56 BPM) gave a small, unstable and volatile increase in heart rate.

Example 14

In contrast to (R)-etomidate, MOC-(R)-etomidate not suppress the adrenal cortex function within 30 minutes after administration.

In previously published messages have been adapted and optimise them is owani the study of adrenal function in rats. Immediately after weighing and installation of a catheter for intravenous injection, each rat was injected with dexamethasone (0.2 mg/kg intravenously; American Regent, Shirley, NY) to inhibit the release of endogenous adrenocorticotropic hormone (ACTH) with the aim of suppressing the formation of corticosterone for the baseline and for inhibiting changing the stress response on the retention and manipulation. The catheter tail vein used for the injection of medicines and fences blood, each time after use was filled with heparin, using 10 u/ml heparin to maintain it in an open condition; to minimize heparinisation rats and sample before the introduction of drugs and blood the heparin solution to fill was removed by soaking a tampon. All fences blood volume was approximately 0.3 ml After administration of all medicines were rinsed with 1 ml of isotonic to ensure full delivery of the drug.

Two hours after treatment with dexamethasone, blood was taken (for registration baseline concentration of corticosterone in the serum), and was administered a second dose of dexamethasone or with intravenous anesthetic, or the media (35% propylene glycol v/v in water) for control. To promote education of corticosterone after five is eleven minutes intravenous gave ACTH 1-24(25 µg/kg; Sigma-Aldrich Chemical Co, St. Louis, MO). Fifteen minutes after administration of ACTH1-24(i.e. 30 minutes after the introduction of the usual means or media) took a second blood sample to measure the concentration of corticosterone in serum-stimulated ACTH1-24. ACTH1-24was dissolved 1 mg/ml in deoksigenirovanii water as the source of the solution was sampled aliquots and frozen (-20°C); fresh aliquot was thawed immediately before use. Rats in all three groups (media, etomidate and MOC-(R)-etomidate) received the same volume of propylene glycol.

Before centrifugation at 3500 g for 5 minutes, the blood samples were allowed to clot at room temperature (from 10 to 60 minutes). Before the second centrifugation at 3500 g for 5 minutes, the serum was carefully separated from any surface obtained fibrin clot using transparent microdosing. After the second centrifugation the resulting layer of serum straw color, not containing clots, was transferred to a new vial for a final centrifugation at high speed (16000 g for 5 minutes) to precipitate any particles or red blood cells. The serum was transferred into a clean vial and quickly frozen (-20°C), leaving to the measurement of corticosterone in 1-2 days. After Ott is tion and inactivation by heating (65°C for 20 minutes) globulin, linking corticosterone was measured baseline serum concentration of corticosterone stimulated ACTH1-24using enzyme-linked immunosorbent assay (ELISA) (Diagnostic Systems Laboratories, Webster, TX) and 96-well plate reader (Molecular Devices, Sunnyvale, CA).

Injection of ACTH1-24stimulated the formation of adrenocorticosteroids, as all rats were observed large concentrations of corticosterone in serum fifteen minutes after administration of ACTH1-24. However, in Fig.9 shows that rats treated with (R)-etomidate for 15 minutes before stimulation of ACTH1-24had significantly lower concentrations of corticosterone in serum than those who received or the media, or equivalent anesthetic dose of MOC-(R)-etomidate. On the other hand, rats that received MOC-(R)-etomidate, had a concentration of corticosterone in the serum, which did not differ from concentrations in rats that received only the carrier.

Example 15

Conclusion on the MOC-(R)-etomidate

MOC-(R)-etomidate is well-tolerated by the analogue of (R)-etomidate, which preserves important favorable pharmacological properties of (R)-etomidate, including rapid onset of action, high efficiency anesthetic action and hemodynamic stability. As (R)-etomidate, it effectively strengthens the function of the GABAAndis eception, what is the intended mechanism of induction of anesthesia. However, in contrast to (R)-etomidate, MOC-(R)-etomidate extremely rapidly metabolized, has ultra-short duration and does not cause prolonged adrenocortical suppression after intravenous bolus injection.

MOC-(R)-etomidate is "soft analogue (R)-etomidate. Soft analog is a derivative of the parent compound, which was specifically designed for that he would have been quick and predictable metabolism after providing their therapeutic effects. Traditionally used soft analogues include the opiate Remifentanil and β-blocker esmolol. Both of these compounds contain labile ester residues, quickly gidrolizuacy to carboxylic acid by esterases, which are found in various organs and/or blood. The half-life of these two drugs in humans 1-2 orders of magnitude shorter than for their neeterificirovannah analogues financila and propranolol. (R)-etomidate also contains ester residue, which is hydrolyzed by liver esterases to a carboxylic acid, but it is a poor substrate for these esterases, which reflects its half-life of several hours. Compared with the structures of Remifentanil and esmolol the structure of the (R)-etomidate suggests two reasons for the low rate of hydrolysis of ester (R)-etomidate. First, ester residue (R)-etomidate attached directly to its imidazole ring, whereas labile ester residues in Remifentanil and esmolol attached to cyclic structures via a spacer consisting of two CH2groups. This spacer can be crucial, as it reduces steric hindrance, giving esterases free access to a carbonyl group. In confirmation of this assumption, when reducing the length of the spacer of esmolol reduced the rate of its hydrolysis of ester.Secondlythe electrons of the carbonyl group (R)-etomidate contribute to the π-electron system, which is distributed on the imidazole ring. This reduces the partial positive charge on the carbonyl carbon atom, making it more weak substrate for nucleophilic attack by esterases. Based on these reasons, we have developed a strategy to add a new ester residue to (R)-etomidate, which is sterically unhindered, and isolated from the π-electronic systems imidazole ring, to obtain the analogue of (R)-etomidate, which will quickly be subjected to metabolism. We expected that this ester residue, similarly remains of Remifentanil and esmolol, will quickly be either hydrolyzed by esterases in different TKA is s and/or in the blood. This was confirmed by our studies of the metabolism of MOC-(R)-etomidatein vitrothat showed that this residue is rapidly metabolized to carboxylic acid in the combined fractions of human liver S9, using traditional analysis of biotransformationin vitro.

Our research has shown that MOS-(R)-etomidate is a General anesthetic in two forms. He has an anesthetic effect, which is 1/4-1/5 part of the power of action (R)-etomidate, and also induces anesthesia through the same receptor mechanism (i.e., strengthening the functions of GABAAndreceptors). Our studies in rats showed that the MOC-(R)-etomidate is an anesthetic with ultra short duration even when multiple ED50loss rectifier reflex. It is considered that recovery of consciousness after anesthesia intravenous bolus of propofol and (R)-etomidate reflects the redistribution of the drug from the brain to other tissues, and is not due to metabolism. Therefore, similar to the tangent of the slope in the relationship between duration of loss rectifier reflex and the logarithm of the anaesthetic dose (Fig.7B) indicates that propofol and (R)-etomidate redistributed from the brain with similar speeds. A much more rapid recovery of consciousness after anesthesia and weak is the slope of this dependence for the MOC-(R)-etomidate means, what's to stop anesthetic action of MOC-(R)-etomidate significant contribution superfast metabolism.

MOC-(R)-etomidate respectively induces a short (30 seconds) a decrease in blood pressure, suggesting that the hemodynamic effects of MOC-(R)-etomidate also be terminated due to metabolism. In addition, we found that the maximum value of this reduction is significantly less after the introduction of MOC-(R)-etomidate than after the introduction of the equivalent anesthetic doses of (R)-etomidate and propofol.

Along with other hydrophobic compounds containing imidazole, (R)-etomidate suppresses the formation of adrenocorticosteroids. The basic mechanism underlying this inhibition is the inhibition of 11β-hydroxylase, an important enzyme in the biosynthetic pathway leading to adrenal cortical synthesis of cortisol, corticosterone and aldosterone. It was hypothesized that (R)-etomidate inhibits 11β-hydroxylase due to competitive binding to steroid precursor in a possible hydrophobic catalytic site of the enzyme. As MOS(R)-etomidate was designed to quickly subjected to metabolism by esterases, giving celinopravno carboxylic acid, we expected that the MOC-(R)-etomidate will not induce after the introduction of long adenocor Talnoe suppression. This assumption was confirmed, within thirty minutes after administration of MOC-(R)-etomidate does not reduce the concentration of corticosterone in serum-stimulated ACTH1-24while the equivalent of an anaesthetic dose of (R)-etomidate significantly reduce. Our results also imply that after administration of a single intravenous dose any effect quickly formed metabolite(s) of MOC-(R)-etomidate on the synthesis of corticosterone is negligibly small.

Although here in detail are presented and described embodiments of the specialist in the art will understand that can be done various modifications, additions, substitutions, etc. without deviating from the invention, and, therefore, it is believed that they are within the scope of the invention as defined in the attached claims, below.

Specialist in the art will also readily appreciate that the present invention is well adapted to carry out the objectives and obtain the final objectives and the advantages mentioned, as well as what this implies. Described here the molecular complexes and the methods, procedures, processing, molecules, specific compounds are preferred options for implementation are illustrative and are not intended to limit the response of the volume of the invention. Changes therein and other uses that will be made by a person skilled in the technical field covered by the invention, is limited by the claims.

Specialist in the art will also be obvious that changing substitutions and modifications of the invention described here may be made without deviating from the scope and essence of the invention.

All the patents and publications indicate the levels of the specialists of the technical field to which the invention relates. All patents and publications incorporated herein by reference to the same extent as if each individual publication was specifically and individually indicated as included in the reference.

Clearly the invention described here can properly be applied in practice in the absence of any element or elements, limitation or limitations which is not specifically described. Here, in each case, any of the terms "including", "mainly comprising" and "consisting of" may be replaced by any of the other two terms. The used terms and expressions are used as terms of description and not of limitation, and it is not intended that the use of such terms and expressions to exclude any equivalents shown and described signs or the t, but it should be understood that various modifications are possible within the stated claims. Thus, it should be understood that although the present invention has been specifically described with preferred embodiments and features, modifications and changes ideas described here can be reviewed by a specialist in the art and such modifications and changes are considered as falling under the scope of the present invention, as defined in the attached claims.

1. The compound of formula (I)

where
R1is the L1C(O)OL2C(O)OT;
R2is unsubstituted C1-C10by alkyl;
L1is the link;
L2is unsubstituted With2-C10alkylene;
T is C1-C10by alkyl; and
its pharmaceutically acceptable salt, a mixture of stereoisomers and enantiomers.

2. Connection on p. 1, where the specified connection is present in the form of a pure enantiomer.

3. Connection on p. 2, where the specified enantiomer is the R enantiomer.

4. Connection on p. 1, where the compound contains two ester groups.

5. Connection on p. 1, where R2is CH3, L1is a bond, L2is CH2CH2and T is CH3.

6. Connected the e on p. 1, where R2is CH3, L1is a bond, L2is CH2(CH2)4CH2and T is CH2CH2CH2CH3.

7. Connection on p. 1, where R2is CH3and L1is the link.

8. Pharmaceutical composition for anesthesia containing a pharmaceutically effective amount of the compounds of formula (I)

where
R1is the L1C(O)OL2C(O)OT;
R2is stands;
L1is the link;
L2is unsubstituted With2-C10alkylene;
T is C1-C10by alkyl; and
pharmaceutically acceptable carrier.

9. The method of providing anesthesia in a mammal, comprising an introduction to the specified mammal the compounds of formula (I) under item 1.

10. The method of providing anesthesia in a mammal, comprising an introduction to the specified mammal the pharmaceutical composition under item 8.

11. The method according to p. 9, where the composition comprises a compound of formula (I), where R2is CH3, L1is a bond, L2is CH2CH3and T is CH3.

12. The method according to p. 9, where the introduction phase is injected from 0.01 mg/kg to 100 mg/kg of the compounds of formula (I).

13. The method according to p. 9, where the aforementioned introduction includes: injection of a single effective dose of the compounds is Oia formula (I).

14. The method according to p. 9, where the aforementioned introduction includes: continuous infusion of the effective dose of the compounds of formula (I).

15. The compound according to any one of paragraphs.1-7 to apply for maintenance of anesthesia in a mammal.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formulae

,

where X is O, NH or N-Rx, and Rx, Ra, Rb, R10a, R11a, R2, R3, R4 are selected from hydrogen, different aliphatic, alicyclic, aromatic, heteroaromatic and functional groups which can be optionally substituted, wherein R4 together with R2 can form a C1-C5alkylene or C3-C5alkenylene fragment. Said compounds are positive modulators of metabotropic glutamate receptor 2 and can be used in medicine.

EFFECT: novel biologically active compounds are efficient when treating a range of diseases of the nervous system which are mediated by the dysfunction of the glutamate receptor.

23 cl, 590 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention refers to an agent for activation of lipoprotein lipase containing a benzene derivative of general formula (1) which is used for preventing and treating hyperlipidemia and obesity. The invention also refers to the benzene derivatives of general formula (1a).

EFFECT: composition improvement.

8 cl, 6 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: present invention discloses a method of producing oligonucleotides, involving the following steps: a) providing a hydroxyl-containing compound of formula (A) wherein B is a heterocyclic base and i) R2 is H, a protected 2-hydroxyl group, F, protected amino group, O-alkyl group, O-substituted alkyl, substituted alkylamino or C4'-O2' methylene bridge; R3 is OR'3, NHR"3, NR"3R'"3, wherein R'3 is a group, protected hydroxyl, protected nucleotide of protected oligonucleotide, R"3, R'"3 are independently amine-protecting groups, and R5 is OH or ii) R2 is H, protected 2'-hydroxyl group, F, protected amino group, O-alkyl group, O-substituted alkyl, substituted alkylamino, C4'-O2' methylene bridge; R3 is OH, and R5 is OR5 and R'5 is a hydroxyl-protecting group, protected nucleotide or protected oligonucleotide or iii) R2 is OH, R3 is OR'3, NHR"3, NR"3R'"3, wherein R3 is a hydroxyl-protecting group, protected nucleotide or protected oligonucleotide, R"3, R'"3 are independently amine-protecting groups, and R5 is OR'5 and R'5 is a hydroxyl-protecting group, protected nucleotide or protected oligonucleotide; b) reaction of said compound with a phosphitylation agent in the presence of an activator of formula (I) (activator I), wherein R is alkyl, cycloalkyl, aryl, aralkyl, heteroalkyl, heteroaryl; R1, R2 is H or together form a 5-6-member ring; X1, X2 are independently N or CH; Y is H or Si(R4)3, where R4 is alkyl, cycloalkyl, aryl, aralkyl, heteroalkyl, heteroaryl; B is a deprotonated acid, to obtain a phosphitylated compound; c) reaction of said phosphitylated compound without separation thereof from a second compound of formula (A), wherein R5, R3, R2, B are independently selected but have the same values as given above, in the presence of an activator II other than I.

EFFECT: improved method.

9 cl, 14 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: present invention relates to a method of producing 5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)benzamine , involving reaction of 4-methyl-1H-imidazole or salt thereof with a compound of formula , where X denotes a halogen and Y denotes NH2, in the presence of a suitable base or corresponding transition metal as a catalyst or combination thereof in a suitable solvent. The invention also relates to other versions of the method of producing a compound of formula (I) and intermediate compounds used.

EFFECT: new versions of the method of producing 5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)benzamine (I), which is an intermediate compound in synthesis of biologically active compounds.

9 cl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a new improved method of producing onium tetrafluoroborates through reaction of an onium halide with trialkyloxonium tetrafluoroborate, trialkylsulphonium tetrafluoroborate or triphenylcarbonium tetrafluoroborate, characterised by that the halide has formula (1) [XR4]+ Hal-, where X denotes N, P, Hal denotes Cl, Br or I and R in each case independently denotes a linear alkyl having 1-8 C atoms, or the halide has formula (2) [(R1R2N)-C(=SR7)(NR3R4)]+ Hal- (2), where Hal denotes Br or I R1-R7 each independently denotes a linear alkyl having 1-8 C atoms, or the halide has formula (3) [C(NR1R2)(NR3R4)(NR5R6)]+ Hal- (3), where Hal denotes CI, Br or I and R1-R6 each independently denotes a linear alkyl having 1-8 C atoms, or the halide has formula (4) [HetN]+ Hal- , where Hal denotes CI, Br or I and HetN+ denotes a heterocyclic cation selected from a group comprising imidazolium pyrrolidinium pyridinium where each of substitutes R1' - R4' independently denotes hydrogen, CN, linear or branched alkyl having 1-8 C atoms, dialkylamine containing alkyl groups having 1-4 C atoms but which is not attached to he heteroatom of the heterocyclic ring.

EFFECT: method enables to obtain products with low content of halides with high purity and high output.

5 cl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there is described a compound of formula I: or its pharmaceutically acceptable salt, where R2 represents (CR3R4)n-NR5R6 and m, p, q, Ar, R1, R3, R4, R5 and R6 are those as specified in the patent claim and defined as selective 5-NT6 and/or 5-NT2A antagonists. There is also described a pharmaceutical composition containing this compound, and application thereof in preparing drugs for treating diseased conditions of central nervous system chosen from psychoses, schizophrenia, manic depressions, neural disorders, memory impairment, attention deficient syndrome, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, malnutrition and Huntington's disease.

EFFECT: preparation of the compounds which can find application in treatment of a diseased condition of central nervous system.

27 cl, 1 tbl, 29 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) and their pharmaceutically acceptable salts and esters. The disclosed compounds have LXR-alpha and/or LXR-beta agonist properties. In formula (I) R1 is hydrogen, halogen; R2 is lower alkyl, flouro-lower alkyl; R3 is hydrogen, phenyl; R4 is hydrogen, hydroxy; R5 is hydrogen; phenyl; R6 is phenyl, a 5-6-member heteroaryl with one or two heteroatoms selected from nitrogen and sulphur, a 9-member bicyclic heteroaryl with a sulphur atom as a heteroatom, which can be optionally substituted with a halogen, or R6 is , R7 is a lower alkyl; R8 is phenyl which is optionally substituted with one substitute selected from a group consisting of halogen, fluoro-lower alkyl, R9-O-C(O)-, R10R11NC(O)-, phenyl-lower alkoxy; R9, R10, R11 independently represent hydrogen or lower alkyl; L is a single bond, lower alkylene or lower alkenylene; m assumes values from 0 to 3; n is equal to 0 or 1.

EFFECT: obtaining a new compound and a pharmaceutical composition which contains the disclosed compound as an active ingredient for therapeutic and/or preventive treatment of diseases.

23 cl, 47 ex

FIELD: chemistry.

SUBSTANCE: invention refers to synthesis of [18F]fluororganic compounds ensured by reaction of [18F]fluoride and relevant halogenide or sulphonate with alcoholic vehicle of formula 1 where R1, R2 and R3 represent hydrogen atom or C1-C18 alkyl.

EFFECT: possibility for mild process with low reaction time and high yield.

21 cl, 2 tbl, 27 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new displaced heterocyclic derivatives that can be used in treatment of diabetes and to reduce the content of cholesterol. In formula m is 1; n is 1; Q is C; A is -(CH2)x2-0-(CH2)x3-, where x2 varies from 1 to 3 and x3 is 0; B is a bond or it is (CH2)x4, where x4 varies from 1 to 2; X represents CH or N; X2, X3, X4, X5, X6 represent C, N, O; provided that one from X2 X3 X4 X5 and X6 represents N; and at least one of X2, X3, X4, X5, and X6 represents C; R1 represents H or C1-C6alkyl; R2 is H; R2a, R2b and R2c can be equal or different and selected from H, C1-C6alkyl, C1-C6alkoxy, halogen or thyano; R3 is selected from phenyloxycarbonile, C1-C6alkyloxycarbonile, phenylcarbinol, phenyl, alkoxy; Y represents CO2R4 (where R4 represents H or C1-C6alkyl); (CH2)m can be not necessarily displaced by 1 substitute.

EFFECT: produced are pharmaceutical composition for treatment of diabetes and to reduce the content of cholesterol.

13 cl, 2 tbl, 22 dwg, 88 ex

FIELD: chemistry of organophosphorus compounds, chemical technology.

SUBSTANCE: invention describes a method for synthesis of monohydroperfluoroalkanes, bis-(perfluoroalkyl)phosphinates and perfluoroalkylphosphonates. Method involves treatment of at least one perfluoroalkylphosphorane with at least one base wherein base(s) are chosen from group consisting of alkali-earth metal hydroxides, metalloorganic compound in useful solvent or at least one organic base and an acid in useful reaction medium. Also, invention describes novel perfluoroalkylphosphonates and bis-(perfluoroalkyl)phosphinates, using novel perfluoroalkylphosphonates and bis-(perfluoroalyl)phosphinates as ionic liquids, catalysts of phase transfer or surfactants.

EFFECT: improved method of synthesis.

18 cl, 19 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a method for preparing 2-methylimidazole involving mixing 40% aqueous glyoxal, acetaldehyde and aqueous ammonia, further recovering an end product by distillation, differing by the fact using 25% ammonia, mixing acetaldehyde and ammonia at temperature 0÷5°C; adding glyoxal preliminary purified from impurities by electrodialysis at temperature no more than 60°C; the agents taken in a ratio of ammonia : acetaldehyde : glyoxal = 2:1:1; the reaction conducted at temperature 90-95°C for 3 hours; besides, the end product recovered by vacuum distillation at residual pressure 0.5-1.5 kPa and vapour temperature 120-140°C preceded by water distillation.

EFFECT: what is developed is the new method for preparing 2-methylimidazole differing by high yield and end product quality, as well as simplified process of recovering and purifying.

2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 4-(2,3-dimethylbenzyl)-1H-imidazole, also known as detomidine, having formula I: , which involves alkylation of trimethylsilyl imidazole with a compound of formula II: , where X: CI, Br, OH, in the presence of titanium tetrachloride in the medium of a chlorine-containing organic solvent, where molar ratio of titanium tetrachloride to N-trimethylsilyl imidazole must be maximum but must not be more than 0.95.

EFFECT: novel method of producing detomidine, characterised by high output of the end product.

1 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to a method of producing 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, also known as medetomidine, having structural formula I: , which involves alkylation of N-trimethylsilyl imidazole with 2,3-trimethylbenzyl chloride in the presence of titanium tetrachloride in the medium of chlorine-containing organic solvents with molar ratio with 2,3-trimethylbenzyl chloride: trimethylsilyl imidazole:TiCl4 equal to 1.0:4.0-5.0:3.6-4.5.

EFFECT: improved method of producing medetomidine, characterised by high output of the end product.

1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel cyclic N,N'-diarylthioureas or N,N'-diarylureas of general formula (1), their optic (R)- and (S)-isomers and their pharmaceutically acceptable salts - antagonists of androgenic receptors. In formula (1), where: X represents oxygen or sulfur atom; m=0 or 1, mR1 represents C1-C3alkyl; R2 and R3 represent hydrogen atom; or R2 and R3 together with carbon atom, to which they are bound, form group C=O; or represents group NH; R4 and R5 represent hydrogen atom; or R4 represents hydrogen atom, and R5 represents methyl; or R4 represents hydrogen atom, methyl, and R5 represents group Zn-Y-R6, in which n=1 or 2, Z represents CH2 or C=0 and Y- oxygen atom or N-CH3, or Y represents C=O, and Z represents CH2; R6 represents hydrogen atom, methyl, benzyl, hydroxygroup or R5 and R4 together with atoms, to which they are bound, form five or sic-member heterocycle, including, at least, oxygen or nitrogen atom, which can be substituted by methyl. Invention also relates to method of obtaining compounds.

EFFECT: invention relates to anti-cancer substance, pharmaceutical composition, medication and method of treating prostate cancer with application of invention compounds.

12 cl, 6 dwg, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) in form of a separate stereoisomer, a mixture of stereoisomers or a racemic mixture of stereoisomers and their pharmaceutically acceptable salts. In formula (I) ring A, C or D is independently completely or partially saturated; each of C1, C4, C11, C12, C15 and C16 is independently substituted with two hydrogen atoms; each of C9 and C14 is independently substituted with a hydrogen atom; R1 represents -OR7 or -N(R7)2. Values of the rest of the radicals are given in the formula of invention. The invention also relates to a pharmaceutical composition with anti-inflammatory activity and contains an effective amount of the disclosed compound and to use of the said compounds to make a medicinal agent with anti-inflammatory activity.

EFFECT: disclosed compounds have anti-inflammatory activity.

23 cl, 47 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel imidazole derivatives of formula (I): and to its salts with acid, where: R1 and R2 represent hydrogen; Q represents (CH2)m-X-(CH2)n-A; A represents direct bond, O, SO2, NR5; X represents direct bond, O, SO2, C(O) or NR5; Z represents group selected from : m and n represent, each independently, 0, 1, 2, 3 or 4; p represents 1, 2, 3 or 4; q represents 0, 1 or 2; dotted line means that R8 and/or R9 can be situated in any position of benzothiophene ring; R3 and R8 represent, each independently, hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alcoxycarbonyl, carboxamido, NR10R11, SO2NR10R11, OSO2NR10R11 or NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10; when Q-Z represents n 0, 1 or 2 and p represents 1, one of R3 and R8 represents hydroxy, nitro, NR10R11, OSO2NR10R11, NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10, CONR10R11, and the other represents hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alcoxycarbonyl, carboxamido, NR10R11, SO2NR10R11 OSO2NR10R11, NR12SO2NR10R11, CO2R10; R4 and R9 represent, each independently, hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alcoxycarbonyl, carboxamido, NR10R11, SO2NR10R11, OSO2NR10R11, NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10, CHO; when p represents 2, 3 or 4, R9 can be similar or different; R6 and R7 represent hydrogen; each R5, R10, R11 and R12 represents hydrogen; when Z represents and p represents 1, then R8 and R9 can also together with phenyl ring form benzoxathiazine dioxide. Invention also relates to pharmaceutical composition and to application of derivatives by any of ii.1-25.

EFFECT: obtaining novel biologically active compounds which possess inhibiting activity with respect to aromatase and/or steroid-sulfatase and/or carboanhydrase.

36 cl, 67 ex, 5 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of imidazole of the formula (I):

or its pharmaceutically acceptable salts wherein X represents -CH2-(CH2)p-, -O-; R1 represents phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, (C3-C7)-cycloalkyl wherein indicated phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, (C3-C7)-cycloalkyl are substituted optionally with 1-3 substitutes taken independently among halogen atom, -OH, halogen-(C1-C6)-alkyl, (C1-C6)-alkyl, (C1-C6)-alkoxy group and OH-(C1-C6)-alkyl; R2 represents hydrogen atom (H) or (C1-C6)-alkyl; R3 represents H or (C1-C6)-alkyl; R4 represents H or (C1-C6)-alkyl; R5 represents H, or R5 and R7 form in common a bond; each R6 represents independently halogen atom, -OH, halogen-(C1-C6)-alkyl, (C1-C6)-alkyl, (C1-C6)-alkoxy group or OH-(C1-C6)-alkyl; R7 represents H, or R7 and R5 form in common a bond; each R8 represents independently -OH, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl or (C1-C6)-alkoxy group; m = 0, 1, 2 or 3; n = 0 or 1; p = 0 or 1; r = 0 or 1; t = 0. Also, invention relates to a method for preparing compounds of the formula (I) and to a pharmaceutical composition showing affinity to alpha-2-adrenoceptors based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof used in aims for treatment of neurological disturbances, psychiatric disorders or disturbances in cognitive ability, diabetes mellitus, lipolytic diseases, orthostatic hypotension or sexual dysfunction.

EFFECT: improved preparing method, valuable medicinal properties of compounds and compositions.

25 cl, 1 tbl, 14 ex

The invention relates to imidazole derivative of the formula (I), where X, Y, R, R2, R3and R4such as defined in the claims

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new compound, namely to (S)-enantiomer of 1'-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxol-7,3'-indole]-2'(1'H)-one of formula (I), and a method for preparing it which is effective for treating diseases and conditions, such as pain, an intensity of which can be reduced or relieved by modulating potential-dependent sodium channel gatings.

EFFECT: invention refers to the pharmaceutical composition of the above compound, methods of treating and a method of relieving an ion flux through the potassium channel gating in a cell.

10 cl, 5 tbl, 6 dwg, 11 ex

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