Therapeutic compounds

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a new (-)-stereoisomer of formula (I) wherein X is H, or its pharmaceutically acceptable salt which agonise GABA receptor, to a pharmaceutical composition on the basis of the presented compound, to a method for preparing the (-)-stereoisomer of formula (I) or its pharmaceutically acceptable salt, to a method for inducing or maintaining general anaesthesia, to a method for promoting pain management and to a method for promoting pain management and to a method for prototyping antiemetic activity with the use of the presented (-)-stereoisomer or its pharmaceutically acceptable salt, as well as to a new diastereoisomer (-)-2,6-di-fluoro-butylphenyl ester of carbamic acid of formula (II) wherein R1 represents a chiral amino group, and X is H, or to its pharmaceutically acceptable salt.

EFFECT: preparing the pharmaceutically acceptable salt which agonise GABA receptor.

14 cl, 15 ex, 8 tbl, 3 dwg

 

The technical field to which the invention relates.

The present invention relates to therapeutic compounds, useful as anesthetics.

The level of technology

Propofol (2,6-diisopropylphenol) is an intravenous sedative/hypnotic agent, is widely used to induce and maintain General anesthesia (General anesthesia), analgesia seriously ill patients and anesthesia procedures (e.g. endoscopy) (Langly, M.S. and Heel, R.C. Drugs, 1988, 35, 334-372). Propofol only moderately soluble in water and is currently sold in 10% soybean oil-based lipid emulsions, like the compositions for parenteral nutrition.

Propofol is an agonist DAWAA(gamma-aminobutyric acid, GABA), activating different receptor subtypes DAWAAwhich are ion channels that carry the anions chloride across cell membranes in the Central nervous system. Despite the fact that propofol is achiral, racemic mixture of a number of dialkylphenols are known agonists of the receptor DAWAA(James et al., J. Med. Chem. 23, 1350, 1980; Krasowski et al., J. Pharmacol. & Exp. Therapeutics 297, 338, 2001). James et al., reports about the discovery of the fact that propofol is predominant in the overall profile compared to other valued counterparts.

Many clinicians prefer propofol of C is its excellent pharmacokinetic and pharmacodynamic profiles, profiles of recovery from anesthesia and recovery of consciousness after anaesthesia. However, undesirable side effects (e.g. respiratory depression, ICU syndrome, injection pain and hemodynamic effects)caused by therapeutic dose or close to it dose greatly limit its usefulness in a variety of clinical situations. This applies in particular to the hemodynamic effects. The introduction of propofol, especially in bolus form often causes a drop in blood pressure without a compensatory increase in heart rate. Some of the clinical condition are incompatible with the use of propofol due to unwanted and potentially harmful hemodynamic consequences. Examples of such conditions include cardiovascular disease, such as coronary artery disease, cardiomyopathy, ischemic heart disease, valvular defect and congenital heart disease. Chronic hypertension, cerebrovascular disease, traumatic brain injury, and old age can make use of propofol difficult or problematic due to its hemodynamic properties. Patients with acute blood loss, dehydration or severe infection, including patients with hemorrhagic shock, hypovolemic shock, or septic shock may be subjected to excessive risk in the actual use of the AI propofol. Hemodynamic properties of propofol may limit its use in patients receiving other medications or treatments, such as spinal anesthesia, epidural anesthesia, or vasoactive drugs.

Disclosure of inventions

The invention provides therapeutic compounds that show similar or improved pharmacological activity compared with propofol, along with improved hemodynamic profile. Accordingly, in one embodiment, the invention provides (-)-stereoisomer of formula (I):

in which X represents H or F, or its salt, or a prodrug.

The invention also provides a pharmaceutical composition comprising

(-)-stereoisomer of formula (I) or its pharmaceutically acceptable salt or prodrug, and a pharmaceutically acceptable carrier.

The invention also provides a method of treating nausea, vomiting, migraine, neurodegenerative conditions of the nervous system (for example, illness of Frederick, Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), a disease Peak etc), injuries to the Central nervous system (for example, fracture of the skull and, as a consequence of edema, shock, concussion, serious the CSOs bleeding in the brain, cut damage, subdural and epidural hemorrhage and spinal cord injury (e.g., mechanical damage due to compression or bending of the spine)), convulsions (e.g., epileptic seizures) or diseases associated with free radicals (e.g., ischemic reperfusion injury, inflammatory diseases, systemic lupus erythematosus, myocardial infarction, stroke, traumatic hemorrhage, cataract formation, uveitis, emphysema, gastric ulcers, neoplasms, radiation sickness, and so on) in an animal, comprising introducing an effective amount of (-)-stereoisomer of formula (I) or its pharmaceutically acceptable salt, or prodrugs of the animal.

The invention also provides a method of inducing or maintaining General anesthesia in an animal, comprising introducing an effective amount of (-)-stereoisomer of formula (I) or its pharmaceutically acceptable salts, or prodrugs of the animal.

The invention also provides a method of promotion of analgesia in an animal, comprising introducing an effective amount of (-)-stereoisomer of formula (I)or its pharmaceutically acceptable salts, or prodrugs of the animal.

The invention also provides a method of treating migraine in an animal, comprising introducing an effective amount of (-)-stereos is a measure of the formula (I), or its pharmaceutically acceptable salts, or prodrugs of the animal.

The invention also provides a method of treating insomnia in an animal, comprising introducing an effective amount of (-)-stereoisomer of formula (I)or its pharmaceutically acceptable salts, or prodrugs of the animal.

The invention also provides a method of promotion anxiolytic effect in an animal, comprising introducing an effective amount of (-)-stereoisomer of formula (I)or its pharmaceutically acceptable salts, or prodrugs of the animal.

The invention also provides a method of treatment of the syndrome according to the animal, including the introduction of an effective amount of (-)-stereoisomer of formula (I)or its pharmaceutically acceptable salts, or prodrugs of the animal.

The invention also provides a method of promotion antiemetic effect in animals, including the introduction of an effective amount of (-)-stereoisomer of formula (I)or its pharmaceutically acceptable salts, or prodrugs of the animal.

The invention also provides a method of Anisimovna GABA receptor comprising contacting the receptor (in vitro or in vivo) with an effective amount of (-)-stereoisomer of formula (I)or its pharmaceutically acceptable salts, or prodrugs.

The invention also given by us is made by way of Anisimovna GABA receptor in an animal, including the introduction of an effective amount of (-)-stereoisomer of formula (I)or its pharmaceutically acceptable salts, or prodrugs of the animal.

The invention also provides (-)-stereoisomer of formula (I)or its pharmaceutically acceptable salt, or a prodrug for use in drug therapy.

The invention also provides the use of (-)-stereoisomer of formula (I)or its pharmaceutically acceptable salts, or prodrugs for the preparation of medicaments for the treatment of nausea, vomiting, migraine, neurodegenerative conditions of the nervous system (for example, illness of Frederick, Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), a disease Peak etc), injuries to the Central nervous system (for example, fracture of the skull and, as a consequence of edema, shock, concussion, severe bleeding in the brain, cut damage subdural and epidural hemorrhage and spinal cord injury (e.g., mechanical damage due to compression or bending of the spine)), convulsions (eg, epileptic convulsions), or diseases associated with free radicals (e.g., ischemic reperfusion injury, inflammatory diseases, systemic lupus erythematosus, myocardial MIC is RDA, stroke, traumatic hemorrhage, cataract formation, uveitis, emphysema, gastric ulcers, neoplasms, radiation sickness, and so on) of the animal.

The invention also provides the use of (-)-stereoisomer of formula (I)or its pharmaceutically acceptable salts, or prodrugs for the preparation of medicaments for the induction or maintenance of General anesthesia in an animal.

The invention also provides the use of (-)-stereoisomer of formula (I)or its pharmaceutically acceptable salts, or prodrugs for the preparation of medicaments for promotion anesthesia of the animal.

The invention also provides the use of (-)-stereoisomer of formula (I)or its pharmaceutically acceptable salts, or prodrugs for the preparation of medicaments for the treatment of migraine the animal.

The invention also provides the use of (-)-stereoisomer of formula (I)or its pharmaceutically acceptable salts, or prodrugs for the preparation of medicaments for the treatment of insomnia in the animal.

The invention also provides the use of (-)-stereoisomer of formula (I)or its pharmaceutically acceptable salts, or prodrugs for the preparation of medicaments for promotion anxiolytic effect in the animal.

The invention also provides the use of (-)-stereoisomer of formula (I), or farmacevtichesky acceptable salt, or its prodrugs for the preparation of medicaments for the treatment of the syndrome according to the animal.

The invention also provides the use of (-)-stereoisomer of formula (I)or its pharmaceutically acceptable salts, or prodrugs for the preparation of drug promotion antiemetic effect in animals.

The invention also provides the use of (-)-stereoisomer of formula (I)or its pharmaceutically acceptable salts, or prodrugs for the preparation of medicaments for Anisimovna GABA receptor in the animal.

The invention also provides a method of synthesis of intermediate compounds disclosed herein, which are suitable for the production of (-)-stereoisomer of formula (I), or salts thereof, or prodrugs

Brief description of drawings

Figure 1 shows the effect on mean arterial blood pressure (mm Hg) (-) stereoisomer of formula (I)in which X represents N, in pigs after intravenous (IV) infusion, compared with propofol.

Figure 2 shows the effect on heart rate (beats per min) (-) stereoisomer of formula (I)in which X represents N, in pigs after intravenous (IV) infusion, compared with propofol.

Figure 3 shows the effect on cardiac output (liters per minute is the one or l/min) (-)stereoisomer of formula (I)in which X represents N, in pigs after intravenous (IV) infusion, compared with propofol.

The implementation of the invention

The present invention provides (-)stereoisomer of formula (I) or its salt or its prodrug, as defined above.

The absolute configuration of this stereoisomer is defined as (R, R).

In one embodiment, X is N. When X is N, a stereoisomer may also be called (R,R)-2,6-di-sec-butylphenol.

It was found that, compared with propofol, (R,R)-2,6-di-sec-butylphenol unexpectedly demonstrates improved activity profile as an anesthetic. In particular, it was found that the compound has a stronger anesthetic action, shows a higher therapeutic index and stores comparable pharmacokinetic profile, for example, shows a similar rate of excretion from the body. The connection may have a less strong effect on blood pressure, heart rate and/or cardiac output. Moreover, I believe that clinical trials will demonstrate that the compound causes less pain during injection than propofol. Pain during injection of propofol correlated with the concentration of propofol in his lipid emulsion carrier. It was found that when including the research institutes in the composition in an identical lipid emulsion concentration of the aqueous phase (R,R)-2,6-di-sec-butylphenol is significantly reduced (up to more than 90%) compared with propofol.

Also unexpectedly, it was found that two other isomer of 2,6-di-sec-butylphenol, (S,S) or (+) and (meso) stereoisomer demonstrate improved hemodynamic profile, along with similar or improved pharmacological activity compared with propofol. However, it was found that enhanced overall activity profile as anesthetic (R,R)-2,6-di-sec-butylphenol is exceptional for this isomer of this dialkylphenol.

Accordingly, the compounds according to the invention are in particular suitable for inducing or maintaining General anesthesia or promotion of anesthesia to the patient. They are especially suitable for anestesiologia patients with hypersensitivity to hemodynamic effects. Such patients include patients suffering from cardiovascular disease, such as coronary artery disease, cardiomyopathy, ischemic heart disease, valvular defect and congenital heart disease; patients suffering from chronic hypertension, cerebrovascular disease or brain injury; elderly patients (e.g., older than 50, 60, 70 or 80 years of age); patients with acute blood loss, dehydration or severe infection, including patients with hemorrhagic shock, hypovolemic shock, or septic shock; and the of patients receiving spinal anesthesia, epidural anesthesia, or vasoactive drugs (see, for example, Reich DL et al, 2005, Anesth play mode display 101, 622). For example, the patient may be a person with a physical condition which according to the classification of the American society of anesthesiologists (ASA) is at least 3. The present invention also considers the introduction of the compounds according to the invention to patients who cannot undergo pre-anesthesia by injection.

When used herein, the term "pharmaceutically acceptable carrier" includes solvents, adjuvants, excipients or fillers.

The term "animal" includes mammals such as humans, Pets, Zoological animals and cattle.

The term "treatment" of a disease or disorder include: 1) improvement of the disease or disorder (i.e., stopping or reducing the development of the disease or disorder or at least one of its clinical symptoms); 2) improvement of at least one physical parameter, which may be imperceptible to the patient; 3) inhibiting the disease or disorder, which can be expressed or physically (e.g., stabilization noticeable symptom)or physiologically (e.g., stabilization of a physical parameter), or both, or (4) delay of onset Il the disorder.

Stereoisomeric purity of the compounds and prodrugs described herein may be installed using conventional analytical methods, well known to specialists in this field of technology. For example, to establish the stereochemical purity of the individual stereoisomer you can use the application of chiral NMR shift reagents, gas chromatographic analysis on a chiral column high-performance liquid chromatography using chiral columns, polarimetry, isotope dilution, calorimetric, enzymatic methods, capillary electrophoresis in chiral gels, education diastereoisomeric derivatives by reaction with chiral reagents and standard method of analysis using accepted analytical methods. Alternative to establish the stereochemical purity of the compounds described herein can be used synthesis using original materials known stereochemical enrichment. In this area other known analytical methods to demonstrate stereochemical homogeneity.

The present invention provides a stereoisomer of formula (I) or its salt or its prodrug in prizemistoj (i.e. enantiomerically enriched form in the centres marked with a "*" in the formula (I). Thus, the invention includes a stereoisomer of formula (I) in the enrichment of the military of the mixture, which contains not more than 45% of the other enantiomer of the compounds of formula (I), which shows, or its salts, or prodrugs. (-)-Enantiomer selected in example 1 below, is a specific stereoisomer of the invention. In some embodiments of the invention the enriched mixture contains not more than about 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, 4%, 3%, 2% or 1% of other enantiomers or diastereoisomers the compounds of formula (I)or its salt or its prodrug. In another embodiment of the invention the enriched mixture contains less than about 1% of the other enantiomer, or diastereoisomeric the compounds of formula (I)or its salt or its prodrug.

Methods for obtaining compounds of formula (I)

As a rule, the compounds of formula (I) can be obtained by using at least three different approaches. In one approach racemic and/or diastereomers the mixture is produced using conventional methods of organic synthesis, or purchased from commercial sources, and the mixture is separated using methods known to experts in the art, such as, for example, fractional crystallization, separation on chiral columns (see example 1 below), the formation and separation of derivatives or their kinetic optical splitting, etc. in order to provide essentially pure stereoisomers of formula (I) or stereoisomers the enriched mixture of compounds of formula (I). Alternative to obtain the compounds of formula (I) can be used in asymmetric synthesis. To obtain essentially pure stereoisomers of formula (I) or stereoisomers enriched mixtures of compounds of formula (I) can be used known chiral precursors using known methods. Other methods include obtaining chiral intermediates, using, for example, the enantioselective hydrogenation, enantioselective recovery and/or enantioselective formation of carbon-carbon links, enzymatic splitting of racemic acetates, etc. with subsequent transformation into a compound of formula (I)using conventional methods of organic synthesis.

In the same way stereoisomer of formula (I) can be obtained with a chiral isocyanate to form a urethane mixture of diastereomers, which can be divided with getting the required diastereoisomer of formula (I) after hydrolysis of the urethane residue.

Therefore, according to another aspect of the present invention is a method of obtaining a (-) stereoisomer of formula (I) or its salt or its prodrug, which comprises carrying out the hydrolysis of diastereoisomer (-)-2,6-di-sec-butylphenyl ether carbamino acid formula

in which R1is the chiral amino is the SCP with the following, if necessary, the formation of free phenol or its salts (such as a pharmaceutically acceptable salt), or its prodrug.

The hydrolysis may be conducted by reaction of a carbamate with a base, such as hydroxide of alkali metal such as hydrolysed potassium or sodium, which gives the salt of the (-)stereoisomer of formula (I), such as a salt of an alkali metal. The free phenol can be obtained by treatment of this salt with acid, such as hydrochloric acid. Chiral amino group may be, for example, chiral 1-arylaminopoly, for example (R)-1-arylaminopoly, such as (R)-l-phenylethylamine.

Urethane starting material can be obtained by reacting the racemic mixture of the corresponding 2,6-di-sec-butylphenol with a chiral isocyanate with a mixture of diastereoisomers containing diastereoisomer (-)-2,6-di-sec-butylphenyl ether carbamino acid; and separating the corresponding diastereoisomer (-)-2-second-butylphenyl ether carbamino acid of formula (II).

Chiral isocyanate may be, for example, chiral 1-relationoriented, for example (R)-1-relationoriented, such as (R)-(+)-1-generatesessionid. The resulting product is a mixture of the corresponding diastereoisomeric 2-sec-butyl-6-isopropylphenyl ether 1-relationsamong acid. And comy diastereoisomer can be separated using chromatography using, for example, silica as stationary phase or by crystallization.

It has been unexpectedly discovered that the use of (R)-(+)-1-phenylethylenediamine in the above method provides very good separation of the stereoisomers of 2,6-di-sec-butylphenol in comparison with other chiral alleluya or sulfonyloxy reagents, such as chiral carboxylic acids or chiral sulfonic acid.

Methods of obtaining stereoisomer of formula (I) or salts thereof are provided as additional embodiments of the invention.

Salt

In cases where compounds are sufficiently acidic salt of the compounds of formula (I) can be used as an intermediate compound for separation and purification of the compounds of formula (I) or enriched mixture. Also suitable may be the introduction of the compounds of formula (I) in the form of pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts include salts that are obtained using conventional techniques well known in the art, for example by reacting a sufficiently acidic compounds of formula (I) with a suitable base, giving a physiologically acceptable cation. For example, you can get a salt of an alkali metal (e.g. sodium, potassium or lithium) or alkaline earth metal (for example the EP, calcium).

The pharmaceutical composition

The pharmaceutical compositions disclosed here, contain the compound of formula (I), revealed here, with the appropriate amount of pharmaceutically acceptable carrier, to provide the form for proper administration patient. The compounds of formula (I) can be incorporated into pharmaceutical compositions and administered to the patient in a number of forms adapted to the chosen route of administration, i.e. orally, parenterally, intravenously, intramuscularly, topically or subcutaneously.

Thus, the compounds of formula (I) can be introduced systemically in combination with pharmaceutically suitable carriers, such as inert solvents or edible media. Such compositions and preparations may contain at least 0.1% of active compound. Undoubtedly, the percentage of the compositions and preparations may vary, and may conventionally be in the range between from about 0.1% to about 60% by weight of this standard dosage forms. The number of active compound in such therapeutically suitable compositions is therefore to achieve an effective dose level.

The compounds of formula (I)described herein typically include pharmaceutical compositions suitable for intravenous administration. The compounds of formula (I) can be relatively what about insoluble in water. Thus, for intravenous administration, the compounds of formula (I) is usually included in the composition in aqueous media using one or more solvents that are immiscible with water, and one or more emulsifiers or surfactants. Certain compositions may include one or more additional components, such as stabilizing agents, modifiers toychest, a base or acid to regulate the pH and soljubilizatory. The composition can also optionally contain preservatives, such as, for example, ethylenediaminetetraacetic acid (EDTA) or sodium metabisulfite. Suitable emulsion oil-in-water containing a preservative, such as EDTA, which can be used together with the compounds described herein are described in U.S. Patent No. 5,908,869, 5,714,520, 5,731,356 and 5,731,355.

In the here described pharmaceutical compositions can be used with a wide range of water-immiscible solvents. Water-immiscible solvent may be a vegetable oil, such as soybean, safflower, cottonseed, corn, sunflower, peanut, castor or olive oil. Alternative water-immiscible solvent can be a complex ether medium - or long-chain fatty acids, such as, for example, mono-, di - or triglyceride, a complex ester combination is redne - and long-chain fatty acids or chemically modified or synthetic substance, such as etiloleat, isopropylmyristate, isopropylpalmitate, esters of glycerin, polyoxyl or hydrogenated castor oil. Water-immiscible solvent may also be oil-sea fish, such as cod liver oil or other oil of fish. Other suitable solvents include fractionated oil, such as fractionated coconut oil or a modified soybean oil. Water-immiscible solvent may include "structured lipids (see, for example, Lipid Biotechnology, T.M.Kuo and H.W.Gardner (eds.). Marcel Dekker, Inc. New York, NY). Many structured lipids available from private providers such as Danisco A/S, Copenhagen Denmark and S&J Lipids, Ostrander, Ohio.

The pharmaceutical compositions described herein can also contain an emulsifier. Suitable emulsifiers include nonionic synthetic emulsifiers, such as, for example, ethoxylated esters, polyoxypropylene-polyoxyethylene block copolymers and phospholipids. You can also use natural phospholipids, such as phospholipids eggs or soy, and modified or artificial phospholipids or mixtures thereof. In some embodiments, the implementation of emulsifiers are the phospholipids of egg and soybean phospholipids. The phospholipids of egg yolk include phosphatidylcholine, lecithin and phosphatidylethanolamine.

F the pharmaceutical formulations described herein may include a lipid emulsion containing from about 0.1% to about 5% (wt./mass.) the compounds of formula (I), from about 5 to about 25% (wt./mass.) water-immiscible solvent and from about 40% to about 90% (wt./mass.) water. The preferred composition contains from about 0.5% to about 2% (wt./mass.) the compounds of formula (I). In one embodiment, the pharmaceutical composition contains from about 0.5% to about 5% (wt./mass.) the compounds of formula (I) and from about 0% to about 50% (wt./mass.) water-immiscible solvent.

The pharmaceutical compositions described herein can also include a stabilizing agent. Anionic stabilizers include, for example, phosphatidylethanolamine conjugated with polyethylene glycol (PEG-PE), and phosphatidylserine, a separate example of which is dimyristoyl phosphatidylglycerol (DMPG). Additional stabilizers include, but are not limited to, oleic acid and its sodium salt, cholic acid and desoxycholic acid and their corresponding salts, cationic lipids, such as stearylamine and oleylamine, and 3/3-[N-(N',N'-dimethylaminoethyl)carbarnoyl]cholesterol (DC-Chol).

The pharmaceutical compositions described herein, can be made isotonic with blood by the inclusion of a suitable modifier toychest. Most often as modifier toychest use is facilitated by the glycerin. The alternative of modifying toychest agents include xylitol, mannitol and sorbitol. Pharmaceutical compositions typically comprise so they had physiologically neutral pH value, typically in the range of 6.0 to 8.5. The pH value can be adjusted by adding a base, for example NaOH or Panso3or in some cases acid, such as Hcl.

The compounds of formula (I) may be included in a composition with a pharmaceutically safe emulsions of the type oil-in-water containing vegetable oil, phosphatidyl emulsifier, usually egg lecithin or lecithin soybeans, and the modifier toychest, such as, for example, Liposyn® II and Liposyn® III (Abbott Laboratories, North Chicago, Illinois) and Intralipid® (Fresenius Kabi AB, Uppsala, Sweden), or other similar emulsions of the type oil-in-water.

The compounds of formula (I) can also be included in the composition of the triglyceride containing esters of at least one fatty acids with medium chain length (C6-C12). In some embodiments, the implementation of triglycerides are esters of C8-C10fatty acid. Triglycerides suitable for inclusion in the compounds of formula (I)include, but are not limited to, Miglyol® (Condea Chemie GmbH (Witten, Germany)). For example, Miglyol® 810 or 812 (Caprylic(C10)/capric (C8) glycerides) is suitable for the composition of the compounds is the second of the formula (I).

In addition, the compounds of formula (I)described herein may be included in similar pharmaceutical compositions of propofol described, for example, in U.S. Patent No. 4,056,635, 4,452,817 and 4,798,846.

Other suitable formulations for use in the present invention can be found, for example, in Remington's Pharmaceutical Sciences, Philadelphia, Pa., 19th ed. (1995).

Therapeutic/prophylactic administration and doses

The compound of formula (I) and/or pharmaceutical compositions can be entered separately or in combination with other pharmaceuticals, including the compounds disclosed here, and/or their pharmaceutical compositions. Compounds disclosed here, can be entered or used by themselves or as a pharmaceutical composition. Certain pharmaceutical composition depends on the desired method of administration, as is well known to a person skilled in the technical field.

Compounds disclosed here, and/or their pharmaceutical compositions can be administered to the subject via intravenous bolus injection, continuous infusion, in the form of tablets for oral administration, capsules for oral use, solution for oral administration, intramuscular injection, subcutaneous injection, transdermal absorption through buccal (cheek) suction, intranasal absorption, inhalation, on jazyce, intracerebral, intrawaginalno, rectally, topically, particularly to the ears, nose, eyes, or skin or any other convenient method known to specialists in this field of technology. In some embodiments, the communication disclosed here, and/or their pharmaceutical compositions are delivered by dosage forms with delayed release, including dosage forms with delayed release for oral administration. The administration can be systemic or local. Known different delivery systems (e.g., encapsulation in liposomes, microparticles, microcapsules, capsules, delivery systems drugs "analgesia, patient-controlled", and so on)that can be used to deliver the compounds disclosed here and/or their pharmaceutical compositions.

The number of compounds disclosed here, and/or their pharmaceutical compositions, which will be effective can be determined by standard clinical techniques known in the art. Introduced a number of compounds disclosed here, and/or their pharmaceutical compositions will of course depend, among other factors, from the subject, which is treated, the weight of the subject, age of the subject status of the subject, the expected activity of a compound, the route of administration and the opinion of the attending physician. For example, the level doses of the programme (R, R) or (-) stereoisomer of formula I to obtain a General anaesthetic may be in the range of from about 1 to about 10 mg/kg Preferred doses for induction of anesthesia range from about 1 to about 2.5 mg/kg of the Preferred maintenance dose ranging from about 1 to about 15 mg/kg/hour. Preferred doses for receiving a sedative effect are in the range from about 0.3 to about 6 mg/kg/hour.

Combination therapy

In certain embodiments the communication disclosed here, and/or their pharmaceutical compositions can be used in combination therapy with at least one therapeutic agent. Compounds disclosed here, and/or pharmaceutical composition and a therapeutic agent can act additively or, more preferably, synergistically. In some embodiments, the communication disclosed here, and/or pharmaceutical composition is administered simultaneously with the introduction of another therapeutic agent, such as, for example, other sedative hypnotics means (for example, etomidate, thiopental, midazolam, dexmedetomidine, ketamine), anesthetics (e.g., desflurane, sevoflurane, isoflurane, nitrous oxide), analgesics (e.g., opioid, such as Remifentanil, morphine, meperidine, hydromorphone, methadone, fentanyl, sulfentanil and the and Alfentanil, or non-analgesic, such as Ketorolac, gabapentin, lidocaine or ketamine), paralytic tools, such as rocuronium, CIS-atrakurium, vecuronium or pancuronium bromide, an antiemetic (e.g., ondansetron, dolasetron, droperidol), cardiovascular drugs (e.g., metoprolol, propranolol, esmolol, clonidine and phenylephrine, ephedrine, epinephrine, norepinephrine, dopamine, diltiazem, atropine, glycopyrrolate, lisinopril, nitroglycerin, sodium nitroprusside, digoxin, milrinone), steroids (e.g. dexamethasone, hydrocortisone, methylprednisolone), antiseptics (for example, Cefazolin, vancomycin), diuretics (eg, furosemide, hydrochlorothiazide, spironolactone), mood-altering means (for example, fluoxetine, aripiprazole) or substances, such as nicotine or tsitizin.

For example, the compounds disclosed here, and/or their pharmaceutical compositions can be entered together with other therapeutic agents. In other embodiments, the communication disclosed here, and/or their pharmaceutical compositions are administered before or after administration of other therapeutic agents.

Prodrugs

The term "prodrug" when used here refers to a compound that can be metabolized or transformed in vivo to provide the compounds of formula (I). About the commonly prodrugs include compounds which are obtained by modification of the phenolic group in the compound of formula (I) to obtain the corresponding compound that can be metabolized or converted in vivo to provide the corresponding compound of formula (I). About prodrugs of phenolic compounds and methods for their preparation have already been reported. For example, see the publication of Patent Applications U.S.№20070015716, 20060287525, 20060205969, 20060041011, 20050239725 and 20050107385.

Other suitable group of prodrugs are discussed in the following publications of International Patent Applications and publications US patents: WO 2005023204; US 2005107385; US 2005004381; WO 2004092187; WO 2004032971; US 2006100163; WO 2006033911; WO 2004033424; US 2005267169; WO 2003086413; US 2002370213; WO 2003057153; US 2001342755; US 2002099013; WO 2002034237; US 2004127397; WO 2002013810; WO 2000048572; US 2006166903; WO 200008033; US 2001025035; WO 9958555 and US 199875356; and in other subsequent publications: Krasowski, M.D. Current Opinion in Investigational Drugs (Thompson Scientific) (2005) 6(1), 90-98; Fechner, J. et aL, Anesthesiology, 2004, 101, 3, 626-639; Altomare C. et al., European Journal of Pharmaceutical Sciences; 2003, 20, 1, 17-26; Sagara, Y. et al., Journal of Neurochemistry; 1999; 73, 6, 2524-2530, and Trapani, G., et al., International Journal of Pharmaceuticals, 1998, 775, 2, 195-204.

As described above, it was found that the other two isomers of 2,6-di-sec-butylphenol, (S,S) or (+) or (meso) isomers of the formula (I) demonstrate improved hemodynamic profile along with similar or improved pharmacological activity compared with propofol. Accordingly, the current image is the buy also provides each of these isomers, their para-fluorine derivatives and their pharmaceutically acceptable salts and their prodrugs, and their pharmaceutical compositions for use as anesthetics.

Each of the (S,S) or (+) or (meso) stereoisomers of formula (I), their salts and their prodrugs can be obtained following the General methods described to obtain the corresponding (R,R) or (-) stereoisomers. For example, the stereoisomers can be separated from racemic compounds using chiral phase chromatography, for example as described in example 2 here. It was found that (S,S) or (+) stereoisomer of 2,6-di-sec-butylphenol can be easily obtained by reacting the racemic mixture of the corresponding 2,6-di-sec-butylphenol with acylhalides (for example, aroylamino, such as benzoyl chloride) to obtain the carbonate mixture of diastereomers, which can be divided with getting the required diastereoisomer of formula (I) after hydrolysis of the carbonate balance. An example of such a method is described in example 5A in the future.

(S,S) or (+) and (meso) stereoisomers of formula (I) may exist, to be included in the composition and entered patients, as described and shown in the example here, for (R,R) or (-) stereoisomers. For (S,S) or (+) stereoisomers, the dose level for General anaesthesia may be in the range of from about 1 to about 12 mg/kg Preferred doses for induction of anesthesia h is formed in the range from about 1.2 to about 4 mg/kg The preferred maintenance dose ranging from about 1.5 to about 30 mg/kg/hour. Preferred doses for receiving a sedative effect are in the range from about 0.5 to about 12 mg/kg/hour. For (meso) stereoisomers dose level for General anaesthesia may be in the range of from about 1 to about 10 mg/kg Preferred doses for induction of anesthesia range from about 1 to about 3 mg/kg of the Preferred maintenance dose ranging from about 1 to about 20 mg/kg/hour. Preferred doses for receiving a sedative effect are in the range from about 0.3 to about 8 mg/kg/hour.

The ability of the compounds of the invention to provide a sedative or hypnotic effect may be installed using standard pharmacological models which are well known in the art. Hemodynamic profile of the compounds of the invention can be determined by standard pharmacological models which are well known in the art.

The invention will now be illustrated by the following non-limiting examples.

Example 1

Department stereoisomer of the compounds of formula (I) via HPLC separation of diastereomeric carbamates 2,6-di-sec-butylphenol.

where:

racemic forms-2,6-di-sec-butylphenol - RA is hemicheskiy 2,6-di-sec-butylphenol;

(R)-(1-isocyanatoethyl)benzene - (R)-(1-isocyanatomethyl)benzene;

pyridine - pyridine;

HPLC-HPLC;

1b. diastereomerically enriched carbamatc - diastereomer-enriched carbamate;

dioxane - dioxane;

2. stereoisomer of Formula (I) (-)-2,6-di-sec-butylphenol - stereoisomer of formula (I) (-)-2,6-di-sec-butylphenol

Synthesis of R-(+) - (1-phenyl-ethyl)-carbamino acid 2,6-di-sec-butylphenyl ether (I):

A mixture of 2,6-di-sec-butylphenol (of 2.06 g, 10 mmol), R-(+)1-phenylethylenediamine (1.47 g; 10 mmol) and 4-(dimethylamino)pyridine (0.06 g; 0.5 mmol) was heated at 100°C in 10 ml of anhydrous pyridine during the night. The reaction mixture was evaporated and the obtained residue was treated with ethyl acetate (75 ml) and 1M aq HCl (100 ml). The organic layer was twice washed in 1M aq Hcl (2×100 ml), brine (100 ml) and dried over anhydrous MgSO4. Evaporation of the solvent gave the carbamate (1) (3 g,85%).

Division of diastereoisomers R-(+) - (1-phenyl-ethyl)-carbamino acid 2,6-di-sec-butylphenyl ester (1b):

Separation by HPLC was performed on a HPLC column with silica gel (250×41.5 mm), the sorbent Si-60A 10 mm, Gradient: hexane-ethyl acetate 0-10% 72 min; flow rate 50 ml/min; loading 1 g (1) in 10 ml of hexane. The fraction with the desired carbamate isomer (1b) was collected and dried (0.18 g, 72%).

The study of optical purity by chiral chromatography

Studies of 2,6-di-sec-butylphenol performed on a column CHIRALCEL OD-H (a 4.6×250 is m) in isocratic mode, mobile phase n-hexane, flow rate 1 ml/min, 20 min, detection at 270 nm. The samples were dissolved in hexano. Carbamates pre-hydrolyzed to 2,6-di-sec-butylphenol at 100°C for 1-2 minutes in a 1:1 mixture of dioxane: 1M NaOH aq. 2,6-di-sec-butylphenol was extracted with ether. The ether layer is evaporated and the residual oil was dissolved in n-hexano.

Synthesis of (-)-2,6-di-sec-butylphenol (2): R-(+) - (1-Phenyl-ethyl)-carbamino acid (-)-2,6-di-sec-BUTYLPEROXY ester (1b) (4.1 g; 11.6 mmol) was dissolved in 100 ml of a 1:1 mixture of dioxane: 1M NaOH aq. The reaction mixture was stirred at 70°C for 15 min Volatile components were removed under reduced pressure to a volume of 50-70 ml pH brought up to 3-4 with 1M Hcl. The phenol was extracted with ether (3×50 ml), washed with 1 M Hcl, brine and dried over anhydrous MgSO4. Evaporation gave the crude product as a yellow oil (2.4 g, ~100%). Did vacuum distillation (120-125°C/~5 mm) (2.1 g, 89%). Optical rotation:(C=2, pentane).

Example 2. Direct separation of the stereoisomers of 2,6-di-sec-butylphenol

Separation of a mixture of stereoisomers of 2,6-di-sec-butylphenol was performed using chiral HPLC. 2,6-di-sec-butylphenol (1 mg/ml in HPLC gradient n-hexane) was injected into chiral HPLC column (Daicel Inc., CHIRALCEL OD-H, 20×250 mm, 5 μm). The separation was performed using isocratic gradient using WAS the gradient of n-hexane as mobile phase at a flow rate of 10 ml/minute at ambient temperature. Peak detection was at 270 mm 2,6-di-sec-butylphenol showed three peaks in the ratio 1:2:1, corresponding enantiomer 1 (the desired stereoisomer), (meso)-2,6-di-sec-butylphenol and enantiomer 2. The separated enantiomer 1 (1 mg/ml) was dissolved in HPLC gradient of n-hexane and introduced into chiral HPLC column (Daicel, Inc., 5 CHIRALCEL OD-H to 4.6×250 mm, 5 μm), chased with isocratic gradient using HPLC gradient n-hexane as mobile phase at a flow rate of 0.7 ml/minute at ambient temperature. Peak detection was at 270 mm, showed a retention time of 17.1 minutes and purity isomer >%99. Optical rotation:. Under the same analytical procedures as for enantiomer 1 enantiomer 2 showed the retention time of 19.6 minutes and purity isomer >about 95%, and (meso)-2,6-di-sec-butylphenol showed the retention time of 18.8 minutes and purity isomer >%96.

Example 3. The composition of

The following table illustrates representative pharmaceutical form containing the compound of formula (I) for therapeutic use.

IngredientThe mass of the portionMass./wt.%
Soybean oil70 g11,71
The soy phospholipids the beans (Lipid S-75) 8,4 g1,41
The compound of formula (I)3.5 g0,59
Glycerinof 15.75 g2,64
Disodium edetate0.035 g0,01
Sodium hydroxide (regulirovanie pH)
Subtotal97,685
Sterile water for injection500 ml83,66
Only597,685100

Example 4. The composition of

The following table illustrates representative pharmaceutical form containing the compound of formula (I) for therapeutic use.

IngredientThe mass of the portionMass./wt.%
Soybean oil70 g11,66
fosfolipidy soybeans (Lipid S-75) 8,4 g1,40
The compound of formula (I)6.0 g1,00
Glycerinof 15.75 g2,62
Disodium edetate0.035 g0,01
Sodium hydroxide (pH regulation)
Subtotal100,185
Sterile water for injection500 ml83,31
Only600,185100

Example 5. Receive (R,R)-di-sec-butylphenol using chromatography for the separation of urethane diastereoisomers

a) (R)-(+) - (1-phenyl-ethyl)-carbamino acid 2,6-di-sec-BUTYLPEROXY ether

Di-sec-butylphenol (available from Acros & AK Scientific) (5 grams (g);

21,1 millimoles (mmol)) azeotrope dried on a rotary evaporator (55°C, 48 Torr), using 5 milliliters (ml) of toluene, then was loaded into a 100-ml three-neck flask equipped with a magnetic stirrer, bratim refrigerator, thermocouple and inlet for nitrogen (N2). Added toluene (10 ml) and 4-dimethylaminopyridine (of 0.085 g; 0.7 mmol). The latter was administered (R)-(+)-(1-generatesessionid (3.5 g; 3,65 ml; 23,63 mmol). The resulting clear yellow mixture was heated under N2at 90°C using a heating mantle, and continued to stir at this temperature, at the same time controlling the development of the reaction by high performance liquid chromatography (HPLC). After completion of the reaction (18-24 hours (h)), according to HPLC, the reaction mixture was concentrated on a rotary evaporator (50-55°C/45 to 50 Torr) to obtain a semi-solid substance (~9.4 g), which was dissolved in hot 2-propanol (18 ml). The solution was allowed to reach ambient temperature, strassle pure (R)-(+) - (1-phenyl-ethyl)-carbamino acid-2,6-di-sec-butylphenyl ether and placed in a refrigerator (4°C) for 24-36 hours for slow crystallization. The precipitated yellow solid was filtered, cooled and dried on the filter funnel within 1-2 hours. The first portion of the product weighed 2.8 g (yield of 37.5%), as was found by HPLC analysis, the purity was greater than (>95 percent area (%). The mother liquid was concentrated on a rotary evaporator to ~2/3 of the original volume (drove 4 ml of propanol) and then was cooled to 0-5°C for 6-8 hours. The second portion of the product was filtered of OHL is established, dried on the filter funnel with additional 2.6 g (yield 34,9%) of product, which was detected by HPLC, was ~88%.

b) (R,R,R)-1-phenylethylamines acid-2,6-di-sec-BUTYLPEROXY ether

In the system for HPLC Agilent equipped with a detector diode matrix and a column Silica Column KROMASIL and 0.46 cm ID × 25 cm length of 10 mm, downloaded 714 mg of racemic R-(+) - (1-phenyl-ethyl)-carbamino kislota-2,6-di-sec-butylphenyl ether, dissolved in 10 ml of hexane/ethyl acetate (98:2)to obtain and 71.4 g/l feed (boot) solution. The sample was suirable hexane/ethyl acetate (98:2) at a speed of 2 ml/min at 25°C. the Fractions containing (R,R,R)-1-phenylethylamines acid 2,6-di-sec-BUTYLPEROXY ether was collected and evaporated under reduced pressure at <55°C. At maximum load (R,R,R)-stereoisomer was collected with a chiral purity of 98.7 per cent diastereomeric excess (de) and total yield of 53%.

C) (R,R)-di-sec-butylphenol

In a 100-ml three-neck flask equipped with a magnetic stirrer, reflux condenser, thermocouple, and inlet for nitrogen (N2), was added a tetrahydrofuran (THF) (9 ml), (R,R,R)-1-phenylethylamines acid-2,6-di-sec-BUTYLPEROXY ether (1 g, 2.8 mmol) and 1.0 M sodium hydroxide (11,4 ml; of 11.4 mmol). The obtained transparent mixture was heated under N2at 55-60°C using a heating mantle and continued paramesh the VAT at this temperature, at the same time controlling the development of the reaction by HPLC. After completion of the reaction (6-8 hour), according to HPLC, the reaction mixture was cooled to 15°C. and filtered to remove the precipitated urea. The filter cake was washed with cold THF (5 ml). The filtrate and wash were combined, acidified to pH 2-3 3.0 M hydrochloric acid (HCl) (3.5 ml). After stirring for 10 minutes (min) was added ether (10 ml), then the resulting mixture was vigorously stirred for 15 min, and then separated the layers. The organic layer was washed 3.0 M HCl (3 ml), brine (5 ml), dried with magnesium sulfate (MgSO4), was filtered to remove the drying agent, and then concentrated on a rotary evaporator to obtain a semi-solid yellow residue which was stirred with methyl tertiary butyl ether (MTBE) (3 ml) for 15 min and then filtered. The residue on the filter is washed with MTBE (2 ml). The filtrate and wash were combined and then concentrated on a rotary evaporator to obtain the title compound as a yellow oil (0.6 g, 100% crude yield), which was found by HPLC had a purity of more than 93%.1H NMR (DMSO-d6), as it was found, consistent with this structure.

Example 5A. Receiving (S,S)-di-sec-butylphenol using chromatography to separate the carbonate diastereoisomers

(a) 2,6-di-sec-butylperbenzoate ether

Di-in the EOS-butylphenol (available from Acros & AK Scientific) was dried on a rotary evaporator (55°C, 48 Torr), using toluene, then was loaded into a 100-millilitre (ml) three-neck flask equipped with a magnetic stirrer, reflux condenser, thermocouple, and inlet for nitrogen (N2). Added toluene and 4-dimethylaminopyridine, and then benzoyl chloride. The resulting mixture was heated under N2at 90°C using a heating mantle, and continued to stir at this temperature, while controlling the development of the reaction by high performance liquid chromatography (HPLC). After completion of the reaction, according to HPLC, the reaction mixture was concentrated on a rotary evaporator (50-55°C/45 to 50 Torr) to obtain a semi-solid substance.

b) (S,S)-2,6-di-sec-butylperbenzoate ether

In the system for HPLC Agilent equipped with a detector diode matrix and a column Silica Column KROMASIL and 0.46 cm ID × 25 cm length of 10 mm, downloaded 2,6-di-sec-butylperbenzoate ether, dissolved in hexane/ethyl acetate (98:2)to receive the feed (boot) solution. The sample was suirable hexane/ethyl acetate (98:2) at 25°C. the Fractions containing (S,S)-2,6-di-sec-butylperbenzoate ether, collected and evaporated under reduced pressure at <55°C To produce low-viscosity oil.

c) (S,S)-di-sec-butylphenol

100-millilitre (ml) three-neck flask equipped with a magnetic stirrer, reflux condenser, those what boparai and inlet for nitrogen (N 2), was placed tetrahydrofuran (THF), (S,S)-2,6-di-sec-butylperbenzoate ether and 1.0 M sodium hydroxide. The resulting mixture was heated under N2at 55-60°C using a heating mantle, and continued to stir at this temperature, while controlling the development of the reaction by HPLC. After completion of the reaction, according to HPLC, the reaction mixture was cooled to 15°C. and filtered to remove the precipitated urea. The filter cake was washed with cold THF. The filtrate and wash were combined, acidified to pH 2-3 3.0 M hydrochloric acid (Hcl) (3.5 ml). After stirring for 10 minutes (min) was added ether (10 ml), then the resulting mixture was vigorously stirred for 15 min, and then separated the layers. The organic layer was washed 3.0 M Hcl, brine, dried magnesium sulfate (MgSO4), was filtered to remove the drying agent, and then concentrated on a rotary evaporator to obtain residue, which was stirred with methyl tertiary butyl ether (MTBE) for 15 min and then filtered. The filter cake washed with MTBE. The filtrate and wash were combined and then concentrated on a rotary evaporator to obtain the title compound.

Biological tests

Pharmacological profile of (R,R)-di-sec-butylphenol was evaluated in comparison with propofol in the tests described in the following examples. In these examples, (R,R)-di-W is p-butylphenol is called the connection 1.

Example 6. The study of hippocampal slices of the rat brain

The ability of compound 1 and propofol to enhance the action of agonists to the receptor g-aminobutyric acid subtype A (DAWAAthe receptor) were examined and compared in the electrophysiological study of hippocampal slices of the rat brain.

Compound 1, obtained as described in example 5, and propofol tested at five concentrations: 0,1; 1, 3, 10 and 30 micromol (mm). Stock solutions of 100 millimolar (mm) of propofol and 100 mm of compound 1, each in DMSO, diluted in saline solution, in order to achieve appropriate concentrations; 30 μm samples contained 0.03% of DMSO; solutions containing 0.1% DMSO, does not have a significant impact on the study sections. Values ES and EC were determined using methods similar to the method described in Casasola et al, 2002, Epilepsy Research 47, 257, with modifications as described below.

Slices of the hippocampus of the rat brain was obtained as follows: Male Wistar rats (100-125 g) were obezbolivatmi with isoflurane and were decapotable, the brain was quickly removed, collected, frozen and cut with the use of the device by vibratome (OTS-4000, Electron Microscope Sciences) on cross sections of a thickness of 400 microns (μm). The slice was transferred to a preheated (33°C)immersed (in liquid) registering the camera, pertusaria at a speed of 2.5-3 ml/min modified artificial cerebrospinal fluid 120 mm sodium chloride, 3.5 mm potassium chloride, 2.5 mm calcium chloride, 1.3 mm magnesium chloride, 1.25 mm of sodium phosphate, 26 mm sodium carbonate, 10 mm glucose, saturated 95% oxygen, pH 7.4). Slices of the hippocampus resulted in a balance in the recording chamber for at least 1 hour.

Electrophysiological study was performed in the following way:

Glass rod electrode (tip diameter of 1-2 μm) was filled with 3M sodium chloride (NaCl) and placed in the layer of pyramidal cells in CA1 of hippocampal slices. A concentric bipolar stimulating electrode 25 μm (SNE-100, Rhodes Medical Supply) were placed in stratum radiatum of area CA1 to stimulate collateral/comissary way of Schaeffer. The responses of a population of pyramidal cells in CA1 were recorded on a device Axoprobe-1A (Axon Instruments, Molecular Devices, Sunnyvale, CA). To obtain the data used pCLAMP 8.2 (Axon Instruments), and analyses used Clampfit (Axon Instruments). Stimulation consisted of a single rectangular pulse duration of 0.3 milliseconds (msec), from Grass stimulator SI 1 Stimulator (Grass Medical Instruments), which were delivered every 20 seconds during the entire experimental period. The intensity of the stimulus was adjusted so as to cause a response 80-90% of maximum. Peak-to-peak amplitude of the response of the population of each stimulus was measured as a measure of excitability of the cells.

Connection 1 and propofol, each is in the presence of ES muscimol (2 μm), each was perfesional sequentially, starting from the lowest to highest concentration, in modified artificial cerebrospinal fluid of the respective slices of the hippocampus. The actions of each concentration was measured from 4 to 7 min after application of compound 1 or propofol, respectively, and it was found that in this time of change in the response was stable. Muscimol (10 μm) was applied after application of compound 1 or propofol, to check the sensitivity of the drug only if connection 1 or propofol did not cause a corresponding inhibition of the amplitude of the spike (total response) populations of CA1 (<90% inhibition). Antagonist DAWAAreceptor channel picrotoxin (50 μm) was applied at the end of the readings to confirm that the response was mediated by GABAAthe receptor.

Data were collected and analyzed using Clampfit software and Excel (Microsoft) and presented as the average and individual values. The degree of population effect (%) was obtained by measuring the amplitude of the population spike (CA1 before (control) and after combined application of muscimol (ES) and compound 1 or propofol (difference normalized to the control and multiplied by 100 to obtain the percent effect).

The data showed that compound 1 was a strong potentiating agent actions agonists on re is atore DAWA Ain hippocampal slices of the rat brain with a value AS 2.5 μm. For propofol is AS was 4.8 μm. Thus, compound 1 behaves like propofol in the research sections of the hippocampus of the brain and really enhances muscimol-mediated response to the receptor-GABAA.

Example 7. Research specificity

Have checked and compared the ability of compound 1 and propofol to interact with a variety of biological targets.

Pharmacological analyses of compounds 1, obtained as described in example 5, and propofol were performed by Cerep, Inc. (Redmond, WA, USA) in their system Profile "explode" ("Diversity Profile"), standard profile 71 receptor (59 peptides, dipeptides or nuclear receptors; 7 ion channels; 5 amine transporters) and 16 enzymes. And the connection 1, and propofol were tested at a dose of 10 μm (therapeutically relevant concentration).

The results showed that compound 1 behaves like propofol for approved 71 receptor and 16 enzymes. For example, connection 1 and propofol (each of them) showed the largest effect (greater than 30% inhibition of the control binding) in a study on the measurement of binding picrotoxinin (active connection picrotoxin) chloride channel isolated from the cerebral cortex of the rat. This ligand-dependent ion channel g-amine is Slaney acid (GABA) is the main target of action of propofol. Moreover, compound 1, and propofol (each of them) showed more than 20% inhibition of the control link relative to only one of the 16 tested enzymes phosphodiesterase 2 (PDE2). There were no significant effects for A2, NMDA, PCP, benzodiazepine or opioid receptors.

Example 8. Pain at the injection Concentration of the aqueous phase

I believe that pain during injection, a common problem with the introduction of propofol caused by propofol present in the aqueous phase of a lipid emulsion (see, for example, Klement W et al, 1991, Br J Anaesth 67, 281). Some studies have reported significant reduction in pain during injection, when the concentration of the aqueous phase of propofol was reduced compared with the amount of propofol in the aqueous phase of Diprivan (see, for example, Doenicke AW et al, 1996, Anesth play mode display 82, 472; Ueki R et al, 2007, J Anesth 21, 325).

Was defined as the concentration of compound 1 in aqueous phase (concentration of the aqueous phase) lipid emulsion composition. This concentration of the aqueous phase was comparable to the concentration of the aqueous phase of propofol included in the same composition and concentration of the aqueous phase of Diprivan® (AstraZeneca, Wilmington, DE, USA).

Was composed of one percent (1%) composition of compound 1 in accordance with example 4, compound 1 was obtained as described in example 5. Composition of 1% propofol was prepared in the same way. Used dip is Ivan (emulsion for injection of 1% propofol) from AstraZeneca.

The concentration of aqueous phase compound 1 and propofol were determined using an ultrafiltration method described in Teagarden DL at al., 1988, Pharmaceutical Research 5, 482. Briefly, four sample composition (0.4 ml) with 1% compound 1, four sample composition (0.4 ml) with 1% propofol and two samples (0.4 ml) of Diprivan placed in microcentrifuge filters Ultrafree®-MC (Millipore, Billerica, MA) and separated the aqueous phase from the liquid phase using microcentrifuge for 15 min at 5000 rpm Concentration of the compound 1 and propofol in the respective aqueous phase quantitatively determined by the method of liquid chromatography/tandem mass spectrometry (LC/MS/MS) in relation to the standard the curves of the compound 1 and propofol using thymol as an internal standard (the analyses were performed Alturas Analytics, Inc., Moscow, ID).

The concentration of the aqueous phase of compound 1 in the composition with 1% compound 1 was 0,38±0.02 μg/ml Concentration of the aqueous phase of propofol in combination with 1% propofol was 6,28±0,41 mg/ml Concentration of the aqueous phase of propofol in Diprivan was 4.1 ág/ml.

These results showed a reduction of 94% in the concentration of the aqueous phase connection 1 in comparison with the concentration of the aqueous phase of propofol in identical compositions and a decrease of 91% in the concentration of the aqueous phase connection 1 in comparison with the concentration of the aqueous phase of propofol in d is privine.

Example 9. Pharmacokinetic studies

Pharmacokinetic (PK) studies were performed on domestic pigs to evaluate the pharmacodynamic effects of compounds 1 and compare them with the pharmacodynamic effects of propofol.

Composition with 1% compound 1, obtained as described in example 5 and was prepared in accordance with example 4 was injected 6 pigs using a 20-min intravenous (IV) infusion at a speed of 0,380 mg/kg/min (total dose of 7.6 mg/kg) and one pig at 0,456 mg/kg/min (total dose 9,12 mg/kg). Plasma concentrations of compound 1 were compared with literature data on propofol with a similar Protocol in which a composition of 1% propofol prepared in the same manner as the composition of compound 1, was injected 5 pigs using a 10-min intravenous (IV) infusion at a speed 0,750 mg/kg/min (total dose of 7.5 mg/kg).

According to this study, compound 1 showed similar pharmacokinetic profile relative to propofol on the model in pigs. Trichostema model best described the connection 1 and the data for propofol. Clearance of compounds 1 exceeded the estimated hepatic blood flow, like propofol. The compound 1 showed similar metabolic pathway of propofol in pigs and humans: glucuronidation in the 1-position with 4-position undergoes hydroxylation with subsequent conjugation CH is koronida and sulfate. Research on the dog with increasing doses showed similar plasma concentrations during insertion compound 1 and propofol, also indicating similar levels of clearance in these types.

Example 10. Anesthetic effects in rats

Researched response to anesthetic dose CC bolus injection of compound 1 compared with propofol in rats.

To determine the start and duration of anesthesia used the approved model of General anesthesia in rodents (see Hill-Venning With et al., 1996, Neuropharmacology 35, 1209; Lingamaneni R et al., 2001, Anesthesiology 94, 1050), as shown by loss of straightening reflex (LORR) and recovery time (the time interval from the return of reflex straightening up until the rat will not be able to cling to and climb a steel frame and normally to move from place to place). Also assessed the minimum dose to achieve the LORR and maximum tolerated dose (MTD).

Composition 1% of compound 1, obtained as described in example 5, and prepared in accordance with example 4, or Diprivan was administered by bolus intravenous (IV) injection of 2.5 ml/min 6 male rats Sprague-Dawley (200-300 g) per dose group for the time required for the introduction of the doses described below. The relative activity was assessed by establishing the dose required to cause 50% of rats loss of reflex straightening (HD50), and dose, n is necessary for to call a 7-minute anesthesia (D7 min). Were investigated dose 1,9; 2,3; 3,0; 7,0; 13,7; 14,0 and 15.2 mg/kg for compounds 1 and 3,5; 4,0; to 7.0 and 14.0 mg/kg of Diprivan.

The results showed that bolus intravenous (IV) administration of the compounds caused a dose-dependent duration of anesthesia in rats. The time of onset (beginning) LORR was less than 15 seconds, when he introduced the appropriate drug in a dose of at least 3 mg/kg for compounds 1 and at a dose of at least 7.0 mg/kg of propofol. Compound 1 did not cause LORR at a dose of 1.9 mg/kg, but caused LORR when all other tested doses. Propofol did not cause LORR in 4 out of 6 rats tested in the dose of 3.5 mg/kg, but caused LORR at all other tested doses. Table 1 compares the results for HD50, D7 min, MTD and therapeutic index (TI; defined here as the ratio of MTD to HD7 min) for compound 1 and propofol. One rat died during the introduction of 14 mg/kg of Diprivan. Two rats died with the introduction of 15.2 mg/kg of compound 1. The recovery time showed a slight correlation with dose, with the exception of high doses of compound 1, which also caused long LORR.

Table 1
Comparison results for HD50, HD7, MTD and TI for compound 1 and propofol, which the s was administered to rats using bolus intravenous (IV) infusion
PropofolConnection 1
HD503.8 mg/kg2.1 mg/kg
HD77,0 mg/kg2,3 mg/kg
MTD<14 mg/kg14 mg/kg
TI<26,1

Thus, compound 1 showed efficacy at lower doses than propofol, and also showed a higher MTD and improved TI compared to propofol.

Also in these tests was evaluated (S,S)-2,6-di-sec-butylphenol obtained in accordance with example 2, in doses 2, 3, 4, 5, 6, 28, 35, 42, 49 and 56 mg/kg table la shows the results for HD50, HD7, MTD and TI for this connection. One of the six rats died with the introduction of 49 mg/kg (S,S)-2,6-di-sec-butylphenol.

Table 1A
Results HD50, Numin, MTD and TI for (S,S)-2,6-di-sec-butylphenol, which was administered to rats using bolus intravenous (IV) infusion
(S,S)
HD504 mg/kg
HD75.2 mg/kg
MTD42 mg/kg
TI8,1

In a separate study, rats were administered 7 mg/kg of compound 1 in crematory or propofol, (S,S)-2,6-di-sec-butylphenol or (meso)-2,6-di-sec-butylphenol (obtained in accordance with example 2) in the same doses and compositions. The results are shown in table Ib. One of 6 rats died with the introduction of 21 mg/kg 1% (meso)-2,6-di-sec-butylphenol, included in cremator; however, the remaining 5 rats showed the duration of anesthesia 34 minutes

(meso)
Table 1b
Comparison of duration of anesthesia (time sleep) after administration to rats at a dose of 7 mg/kg compound 1 and propofol, (S,S)-2,6-di-sec-butylphenol and (meso)-2,6-di-sec-butylphenol using bolus intravenous (IV) infusion
Sleep time
Propofol7,1 min
Connection 123 min
(S,S)6,3 min
12,7 min

Thus, the activity of (S,S)-2,6-di-sec-butylphenol was similar to that of propofol. Activity (meso)-2,6-di-sec-butylphenol was improved compared with propofol. Both stereoisomer showed improved MTD and therapeutic index compared with propofol.

Example 11. Anesthetic and hemodynamic effects in dogs breed Beagle.

Study with higher doses was performed on dogs to demonstrate anesthetic and hemodynamic effects of bolus intravenous (IV) administration of compound 1 compared to propofol.

The endpoints in this study was dependent on the dose of induction, duration, depth and quality of anesthesia and hemodynamic effects of bolus intravenous (IV) administration of compound 1 or propofol. Used a composition of 1% of compound 1, obtained as described in example 5 and was prepared in accordance with example 4, and the composition of 1% propofol, composed in the same way.

Electroencephalographic (EEG) measurement of the depth of anaesthesia was performed using the most interesting index (BIS), which is one of several systems used to measure the effects of anesthetic drugs on the brain, and in order to follow changes in the level of anesthesia or anestezi is. BIS is a mathematical algorithm that analyzes the data from the EEG, and the result is a single number from 100 (full consciousness) to 0 (isoelectric EEG). Other assessments included the scale sedation, clinical observations, blood pressure, electrocardiogram (ECG) and oxygen saturation.

Dog breeds Beagle (male, 2-4 years old, 8-10 kg) implanted ports for vascular access. During surgical implantation of ports dogs head shaved, mark for placement of EEG electrodes and injected BOTOX® (Allergan, Inc., Irvine, CA; purified complex Botanichesky toxin type a): just entered to 40 units per dog for 5 intramuscular (IM) injection through the eyebrow. Injections were intended to suppress muscle movements and electromyographic (EMG) interference with the signal BIS.

The study was cross. Each dog received from 2 to 4 increasing bolus intravenous (IV) doses (entered within 60 seconds) compound 1 or propofol, separated, at least 30 minutes (or until the dog does not Wake up) until then, until the MTD is reached. MTD was defined as the dose which reduced mean arterial blood pressure (MAP) of 50% or to the value of less than 50 millimeters of mercury (mm Hg). All animals received additional oxygen and, if the hat ventilatory support after 4 minutes of apnea.

Depth of anesthesia was determined by assessing the presence or absence lash (wagging tail) reflex, response to a slight bump between the eyebrows or auditory stimulus, the compression of the finger (toe pinch), and respiration. The presence of each characteristic considered as 1 and absence as 0. This gave the possibility to calculate an aggregate score sedative effect over multiple time points for 30 min between doses (5=revival, 0=apnea/deep anesthesia). The quality of anesthesia was assessed, noting the smooth induction (anesthesia), using a qualitative assessment of muscle tone and the presence of involuntary movements. Cases of involuntary movements (e.g., during "exit") was calculated as the presence or absence throughout the observed period for each dose. BIS and hemodynamic effects were analyzed using 2-factor dispersion analysis method ANOVA followed by t-test with correction of Bonferroni for multiple comparisons actions time and dose.

A. Anesthetic effects

The ability of compound 1 and propofol entered using bolus intravenous (IV) infusion to induce dose-dependent anesthesia spontaneously breathing dogs breed Beagle without sedation (3,3-30 mg/kg/dose; 1-10 dogs per dose), shown in table 2. On the E. of the 3 dogs, which was administered 15 mg/kg of propofol, reached MTD at 15 mg/kg Therefore, only 1 dog was given a dose of 30 mg/kg of propofol.

Table 2
Dose-dependent duration of anesthesia (sleep) after a bolus intravenous (IV) infusion to dogs compound 1 and propofol
DosePropofolConnection 1
5 mg/kg13 min24 min
10 mg/kg28 min43 min
15 mg/kg43 min77 min
30 mg/kg69 min105 min

Also the data showed that anesthesia was induced within 1 minute, at all doses of compound 1 and propofol. The duration of anesthesia as measured by the sleep time was longer with compound 1 than with propofol in all doses. An aggregate score sedation showed approximately equivalent to the depth of anesthesia of both drugs, and propofol, and compound 1 at a dose of either the 5 mg/kg There were no significant differences between BIS values in dogs, which were administered compound 1 at a dose of 10 mg/kg or propofol at a dose of 10 mg/kg or 15 mg/kg Compound 1 caused a greater effect on the BIS in doses of at least 15 mg/kg, but these doses are very high, and potentially not clinically relevant. The quality of anesthesia (smooth induction of anesthesia, a qualitative assessment of muscle tone, the presence of involuntary movements) compound 1 was similar to that of propofol.

Also in this test were evaluated (S,S)-2,6-di-sec-butylphenol and (meso)2,6-di-sec-butylphenol obtained in accordance with example 2. Table 2A shows the dose-dependent duration of anesthesia (sleep time) for these compounds.

Table 2A
Dose-dependent duration of anesthesia (sleep) after a bolus intravenous (IV) infusion to dogs (S,S)-2,6-di-sec-butylphenol and (meso)2,6-di-sec-butylphenol
Dose(S,S)(meso)
5 mg/kg8 min25 min
10 mg/kg24 min36 min
15 mg/kg50 min55 min
30 mg/kg50 min58 min

Also the data showed that anesthesia was induced for 1 min at all doses (S,S)-2,6-di-sec-butylphenol and (meso)2,6-di-sec-butylphenol. The duration of anesthesia as measured by the sleep time was similar to propofol for (S,S)-2,6-di-sec-butylphenol and long for (meso)2,6-di-sec-butylphenol. The quality of anesthesia (S,S)-2,6-di-sec-butylphenol was similar to propofol, but it was worse for (meso)2,6-di-sec-butylphenol.

Hemodynamically effects: blood pressure

Hemodynamic data, such as mean arterial pressure (MAP)were recorded on a basic level 1, 2, 4, 8, 15, 20 and 30 minutes Compound 1 was administered in doses of 5, 10, 15 and 30 mg/kg, respectively, 3, 6, 6 and 3 dogs. Propofol was administered in the same doses of 3, 5, 5 and 1 of the dogs, respectively. Only 1 dog received 30 mg/kg of propofol, as a criterion MTD was achieved at a dose of 15 mg/kg in two animals. Data were analyzed using 2-factor dispersion analysis method ANOVA followed by t-test with correction of Bonferroni for multiple comparisons.

Comparison data showing the lo, that propofol caused a significantly stronger effect on the MAP than compound 1. Table 3 represents an example in which the percentage changes in mean arterial pressure (MAP %) from baseline 4 min after bolus intravenous (IV) injection of 10, 15 or 30 mg/kg compound 1 compared with changes in MAP %caused by some doses of propofol.

Table 3
Dose-dependent change in mean arterial pressure, measured as the change in MAP % from baseline values 4 min after bolus intravenous (IV) administration to dogs of compound 1 or propofol
DosePropofolConnection 1
10 mg/kg-22%+11%
15 mg/kg-32%-25%
30 mg/kg-66%*-41%
*Only 1 dog was tested at the dose of 30 mg/kg of propofol, whereas 2 dogs who reached criterion MTD dose of 15 mg/kg of propofol.

Also in this test assessed the (S,S)-2,6-the-sec-butylphenol and (meso)2,6-di-sec-butylphenol, obtained in accordance with example 2. Comparison of the data showed that propofol had a much greater effect on the MAP, than (S,S)-2,6-di-sec-butylphenol and (meso)2,6-di-sec-butylphenol. Table 3A provides an example that compares the change MAP % from baseline values 4 minutes

Table 3A
Dose-dependent changes in mean arterial pressure, measured as the change in MAP % from baseline values 4 min after bolus intravenous (IV) administration to dogs (S,S)-2,6-di-sec-butylphenol and (meso)2,6-di-sec-butylphenol
Dose(S,S)(meso)
10 mg/kg+7%+5%
15 mg/kg+5%+15%
30 mg/kg0%-16%

Example 12. Anesthetic and hemodynamic effects on dogs mongrel

This study compared the effect of total intravenous anesthesia on chronically equipped with instrumentation dogs mongrel, which was introduced connection 1 or propofol. Evaluation included anal is C hemodynamic parameters, such as blood pressure, heart rate, cardiac output, and clinical biochemical parameters and EEG studies.

Composition 1% of compound 1, obtained as described in example 5 and was prepared in accordance with example 4, and Diprivan (injectable emulsion 1% propofol) compared to adults (at least 9 months of age; approximately 20-40 kg) dogs mongrel.

General anesthesia was caused in dogs intravenous (IV) administration of 7 mg/kg of Diprivan, dogs trehearne incubated and mechanically ventolinbuy. General anesthesia was maintained with the use of end-tidal (at the end of a quiet exhalation) 2.2% sevoflurane in oxygen. Thoracotomy was performed in the fifth intercostal space on the left, and filled with heparinized catheters were placed in the proximal descending thoracic aorta (blood pressure sensor R50 Gould, Oxnard, California) and in the right and left artery to provide BB access. Ultrasonic sensor time flow (T, Transonic Systems, Ithaca, NY) was placed around the ascending thoracic aorta. 20 kHz streaming Doppler probe (Model HDP-20-3 .5, Triton Surgical Technologies, San Diego, California) was placed around the left anterior descending coronary artery. Six sonomicrometry crystals MHz (Hartley, Houston, Texas) were implanted in abandoned. Precision mi is romanones (P7, Konigsberg Instruments, Pasadena, CA) was inserted into the left ventricle. Hydraulic vascular obturator (In Vivo Metric Systems, HEALDSBURG, California) was positioned around the thoracic inferior Vena cava. The management of technology was displayed on the surface of the chest wall was closed in layers, and pneumothorax was evacuated. The dogs were given a recovery period of at least 7 days before the experiments and were given the opportunity to adapt to standing in supporting the bandage during the recovery period.

The dogs were hungry during the night. Waking the dogs were placed in a support bandage and inserted needle electrodes for recording ECG in lead II. Electrodes for leads with the skull was placed to record EEG (MR, Biopac Systems, Goleta, Calif.) at three bipolar recording configurations, which measured the frontal, temporal, parietal and occipital areas. Then the dog got CC bolus of 500 ml of normal saline, then intravenous (IV) infusion of normal saline was established with a speed of 3 ml/kg/h (60 to 120 ml/hour for the dog) in the continuation of the experiment. The dog was allowed to stabilize for 30 minutes. EEG was recorded continuously during the experiment. Blood gases and pH, and chemical analyses included pH, ro2, sO2 , pCO2tCO2, carbonate, potassium, sodium and excess basis, and measured immediately after blood collection using the analyzer estimates the gas and electrolyte composition of the blood (ABL-505, Radiometer, Copenhagen). Clinical biochemical blood tests included albumin, albumin/globulin, alkaline phosphatase, alanineaminotransferase (SGPT), aspartataminotransferaza (SGOT), alkaline, direct bilirubin, urea nitrogen blood BUN, the ratio of BUN/creatinine, calcium, chloride, cholesterol, ck, creatinine, globulin, glucose, phosphorus, potassium, sodium, sodium/potassium, and total protein. After stabilization of the recorded measurements of EEG, hemodynamics, ECG and blood gases. Took blood samples for analysis of parameters RK and clinical chemistry and caused the loop pressure-volume data were recorded.

Immediately after baseline measurements dogs received 4 mg/kg (1 dog) or 5 mg/kg (6 dogs) intravenous (IV) bolus dose of compound 1 or 7 mg/kg intravenous (IV) bolus dose of propofol (7 dogs) for 1 minute to induce General anesthesia. After the introduction in the state of anesthesia of dogs incubated tracheal and mechanically ventolinbuy using 50% oxygen in nitrogen during the infusion of the medicinal product and periods of recovery. Starting with 4 minutes after the bolus dose, dogs that receive is whether the bolus connection 1, has introduced a series of four 15-minute intravenous (IV) infusion with a speed of 0.25; 0.5; 1.0 and 2.0 mg/kg/min connection 1 gradually (in a stepwise crossover fashion); the same Protocol used for dogs that have received a bolus of propofol, except that propofol poured at the specified rate and time (introduction). MAP was monitored continuously, and dosing immediately stopped if the MAP decreased below 50 mm Hg at any time, or if heart rate was over 200 beats per minute. Dosing stopped at one of the dog at the end of the period of infusion of compound 1 at a dose of 1.0 mg/kg/min and the other two dogs during the period of infusion of compound 1 at a dose of 2.0 mg/kg/min At the end of each 15-minute infusion were recorded measurements of EEG, hemodynamics, ECG and blood gases, blood samples were taken for the study of Kazakhstan and called loop pressure-volume data were recorded. After dosing, the dogs were given a chance to recover. When the subjective determination of clinical parameters indicated sufficient recovery from General anesthesia, ventilation was stopped, the trachea was extubated. Noted the time exteberria trachea. 30 minutes after the final infusion were recorded EEG, hemodynamic parameters, ECG and blood tests on gases and acidity, took blood samples for RK and caused a loop on the pressure-volume data were recorded.

Were determined concentration of the compound 1 and propofol in the plasma of dogs and were estimated concentration of 5 metabolites (1 oxidation, 3 glucuronide-conjugated 1 and the sulfate-conjugated), using liquid chromatography (LC) and tandem mass spectrometry (MS/MS) (made at Alturas Analytics).

The results showed that the data of the blood gases and pH biochemical and clinical data were sustainable. EEG analysis showed dose-dependent sedative narcotic effect and has not been confirm convulsive or pesudomonas activity. All dogs were (recovered) after General anesthesia with the same speed, regardless, have introduced their connection 1 or propofol. Connection 1 and glucuronide metabolites in the 1-position and 4-position have been found in the plasma. Plasma concentrations were comparable with the mode of introduction of the drug.

On this model at therapeutically relevant doses, the results of the EEG showed a stronger anesthetic effect of compound 1 compared to propofol. There were no statistically significant differences between MAP and heart rate for compound 1 and propofol. Cardiac output in dogs receiving propofol, was significantly reduced from baseline; in contrast, dogs, polucha is their connection 1, showed no statistically significant reduction in cardiac output.

Example 13. Anesthetic and hemodynamic effects in pigs

Anesthetic and hemodynamic effects of compound 1 and propofol were compared on a shot-ventilated pigs, which intravenous (IV) depositing the composition with 0.5% of compound 1, obtained as described in example 2 and prepared in accordance with example 6, or Diprivan emulsion of 1% propofol injection). Evaluation included EEG measure the depth of anesthesia using BIS, pharmacokinetic indices, blood pressure, ECG, heart rate, cardiac output, body temperature and oxygen saturation.

The experiments were conducted at a commercial swine farming of both sexes (average weight of 33.6 kg). Anesthesia was caused by isoflurane. Intravascular access received through the ear vein. Each pig were incubated and mechanically ventolinbuy. The oxygenation of the tissue was controlled by continuous pulse oximetry with the placement on the tongue. For ventilation was monitored using the analyzer of the inhaled/exhaled air, which measured the concentration of oxygen, carbon dioxide and strong inhalation anesthetic. The settings ventilation if necessary regulated to maintain Usto the steady state.

Continuous level of anesthesia was achieved with the help izoflurana and infusion pancuronium (10 mg/hour). ECG was monitored throughout the study. Arterial blood pressure was monitored via a catheter in the left femoral artery. MAP, systolic and diastolic blood pressure and heart rate were recorded every 5 seconds. In the internal jugular vein was placed pulmonary arterial catheter for thermodilution assessment of cardiac ejection and the temperature of your blood. Maintained body temperature at 37°C. For monitoring EEG instrument used sticky electrodes in the frontal-occipital areas (Aspect Medical, Norwood, mA, USA).

The plan of the experiment consisted of 30-minute stabilization period, with subsequent intravenous (IV) infusion of compound 1 (0,384 mg/kg/min × 20 min) or propofol (0,750 mg/kg/min × 10 min). For appropriate infusion was followed by a 180-minute washout period. Blood samples for hemodynamic measurements and for pharmacokinetic analysis were taken prior to infusion, every 2 min during the infusion of compound 1 or propofol and with repeated intervals during the washout period. Time and rate of leaching compound 1 and propofol were installed in advance in order to cause maximum reduction of BIS (<10) during the period of infusion. Samples of the art the state of blood for determination of pH, Rho2, RNO2, glucose, potassium, and lactate were measured at the baseline level prior to the infusion of compound 1 or propofol during the infusion and every hour after infusion.

A. Anesthetic effects

Connection 1 and propofol caused maximum inhibition BIS (<10) when intravenous (IV) infusions 0,384 μg compound 1 within 14,7±3,8 min (kg / min) and 0,750 mg of propofol during 9,4±1,9 min (kg / min), respectively. The effect on the EEG was reversible, and return to the base level occurred within 60 minutes. The area under the curve (AUC) of compound 1 required to achieve maximum pharmacodynamic effect (Emax)was significantly less than for propofol (51,5+15,5 against 108,7+24,3 μg-min/ml, respectively). In conclusion, the data showed that compound 1 was more effective than propofol.

B. Hemodynamic effects

Mean arterial pressure and heart rate were measured at intervals throughout the intravenous (IV) infusion and washout" connection 1 (0,384 mg/kg/min, 5 pigs) and propofol (0,750 mg/kg/min, 6 pigs). The results are shown in figures 1 and 2, respectively. Figure 3 compares the cardiac output caused by compound 1 compared with propofol. In pigs, which were administered compound 1, took samples of arterial blood for blood gases and pH, and biochemical analysis is the study of blood; average values are presented in table 4.

Table 4
The average values of the blood gases and pH and biochemical analysis of blood
MinPHRNO2Rho2ABECPotassiumGlucoseLactate
07,486138,83905,63,8099,61,43
47,502737,24105,83,71102,91,24
207,506636,8419the 5.73,84102,01,20
80 7,494337,5402of 5.44,0099,71,01
1407,480337,23994,14,10100,70,95
2007,464137,63563,24,06102,40,96

ABEC relates to acid-base excess, fixed. Baseline values of MAP and HR did not differ between compound 1 and propofol. Both compounds reduced MAP, but propofol caused a significantly greater reduction in MAP (66±4)than compound 1 (106±3) (p<0,001). The lowest value of HR measured for propofol (88+6 beats / min)was significantly lower than the lowest value HR measured for compounds 1 (129±6 beats / min) (p<0,5). Both values and MAP, and HR returned to baseline value after termination of the infusion of compound 1 or propofol. No considerable differences were observed in reducing cardiac output, caused connection is receiving 1 compared with propofol.

Table 4 shows that all values of blood gases and pH, and biochemical blood tests were within normal limits: compound 1 did not cause significant metabolic changes, such as metabolic acidosis or elevated lactate.

Example 14. Antiemetic activity

Compound 1 was tested for antiemetic activity in ferrets and compared with the activity of propofol.

Males descented (odorless) ferrets weighing 1.0-1.5 kg with ports for vascular access in the jugular vein contained at cycle day/night 12 hour/12 hour at a controlled temperature with unlimited access to water and food ad libitum). Every day throughout the study, ferrets were fed one hour before the dose of the substance. Just before the introduction of the dose of the substance water and food was removed. Composition 1% of compound 1, prepared as described in example 2 and prepared in accordance with example 5, or Diprivan was administered to ferrets with intravenous (IV) infusion; see Wyim RL et al, 1993, Eur J Pharmacol 241, 42 re DIPRBBAN administration in ferrets. After the introduction of compound 1 or Diprivan animals were placed in clean, clear cell (with lids) and left free during the 45-min period of observation (observation conducted "blind" regarding specifically applied impact).

Vomiting in ferrets different rhythmic C is mi abdominal muscles, connected or with oral expulsion of solid or liquid substances from the gastrointestinal tract (i.e., vomiting), or movements that do not include the passage of substances (i.e., retching and vomiting). Cases of retching and/or vomiting were considered as separate cases, when the interval between retching and/or vomiting was 5 sec.

Promotionsnew activity of compound 1 or propofol were studied in 6 ferrets (one drug) as follows: the ferrets were given anesthesia by isoflurane inhalation. Connection 1 or propofol was administered intravenous (IV) infusion over 15 min at a speed of 1 mg/kg/min After infusion for ferrets were observed continuously for 45 minutes, counting the number of cases of vomiting and retching and vomiting.

Antiemetic activity of compound 1 or propofol were studied in 6 ferrets (one drug) as follows: the ferrets were given General anesthesia with isoflurane, injected compound 1 or propofol by 15 min intravenous (IV) infusion at a speed of 1 mg/kg/min After the infusion was subcutaneously injected with 0.5 mg/kg of morphine sulfate, ferrets were observed within 45 minutes, as described above. Another six ferrets were introduced only 0.5 mg/kg morphine sulfate subcutaneously.

One morphine sulfate (0.5 mg/kg) had progamatically activity in ferrets, drive the 15 cases of vomiting and 157 cases of heaves. Compound 1 did not cause any number of cases of vomiting or retching and vomiting, when it was administered alone or in the presence of morphine. In ferrets, which propofol and morphine sulfate, counted, 3 cases of vomiting and 47 cases of heaves. Consequently, compound 1, and propofol reduced the share of cases of vomiting and retching in the presence of morphine.

All publications, patents and patent documents are included in this description by reference as if included in this description separately. The invention is described with reference to various specific and preferred options for implementation and methodology. However, it should be clear that you can make many changes and modifications, but stay in the spirit and framework of the invention.

1. (-)-Stereoisomer of formula (I):

where X is H; or its pharmaceutically acceptable salt.

2. The pharmaceutical composition, the introduction of an effective amount of agony which the GABA receptor, containing the compound according to claim 1 and a pharmaceutically acceptable carrier.

3. The pharmaceutical composition according to claim 2, which is included in the composition for intravenous injection.

4. The pharmaceutical composition according to claim 3, which is included in the composition as a lipid emulsion.

5. Method of inducing or maintaining General anesthesia the animal, including the introduction of animal efficiency the effective amount of (-)-stereoisomer of formula (I):

where X is H; or its pharmaceutically acceptable salt.

6. Method of promotion anesthesia of the animal, including the introduction to the animal an effective amount of (-)-stereoisomer of formula (I):

where X is H; or its pharmaceutically acceptable salt.

7. The compound according to claim 1, which agony receptor GAB, for use in drug therapy.

8. The compound according to claim 1 for inducing or maintaining General anesthesia the animal.

9. The compound according to claim 1 for promotion anesthesia of the animal.

10. The method of obtaining (-)-stereoisomer of formula (I) or its pharmaceutically acceptable salt, which comprises the hydrolysis of diastereoisomer (-)-2,6-di-sec-butylphenyl ether carbamino acid of formula (II)

where R1represents a chiral amino group, and where X is H, followed, if necessary, the formation of free phenol or its pharmaceutically acceptable salt.

11. Diastereoisomer (-)-2,6-di-sec-butylphenyl ether carbamino acid of formula (II)

where R1represents a chiral amino group, and where X is N.

12. Diastereoisomer according to claim 11, where R1is (R)-1-relationiship.

13. Method of promotion antiemetic asset the spine of the animal, including the introduction of the animal (-)-stereoisomer of formula (I):

where X is H; or its pharmaceutically acceptable salt.

14. A method for the treatment of nausea or vomiting in an animal, including the introduction of the animal (-)-stereoisomer of formula (I):

where X is H; or its pharmaceutically acceptable salt.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula used as herbicides, in which Q1 is H or F; Q2 is a halogen provided that when Q1 is H, Q2 is Cl or Br; R1 and R2 independently denote H, C1-C6-acyl; and Ar is a polysubstituted aryl group selected from a group consisting of

a) , b) , c) in which W1 is a halogen; X1 is C1-C4-alkyl, C1-C4-alkoxy, C1-C4-halogenalkyl, -NR3R4; Y1 is C1-C4-alkyl, C1-C4-halogenalkyl, halogen or -CN, or when X1 and Y1 are taken together denotes -O(CH2)nO-, in which n=1; and R3 and R4 independently denote H or C1-C4-alkyl; W2 is F or Cl; X2 is F, CI, -CN, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylthio, C1-C4-alkylthionyl, C1-C4-alkylsulphonyl, C1-C4-halogenalkyl, C1-C4-halogenalkoxy, C1-C4-alkoxy-substituted C1-C4-alkyl, C1-C4-alkoxy-substituted C1-C4-alkoxy, -NR3R4 or fluorinated acetyl; Y2 is a halogen, C1-C4-alkyl, C1-C4-halogenalkyl or -CN, or when W2 is F, Xz and Y2, taken together, denote -O(CH2)nO-, in which n=1; and R3 and R4 independently denote H or C1-C6-alkyl; Y3 is a halogen or -CN; Z3 is F, CI, -NO2, C1-C4-alkoxy, -NR3R4; and R3 and R4 independently denote H; derivatives on the carboxyl group which are suitable for use in agriculture.

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19 cl, 7 tbl, 69 ex

FIELD: chemistry.

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FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to phenolic compounds, derivatives of dialkoxyethanals that are intermediate substances in organic synthesis and can be used as cross-linking agents of phenolic type no evolving formaldehyde also. Phenolic compounds are described of the general formula (I):

wherein: R means (C3-C17)-dialkoxymethyl, 1,3-dioxolan-2-yl substituted possibly at positions 4 and/or 5 with one or some (C1-C8)-alkyls, or 1,3-dioxane-2-yl substituted possibly at positions 4 and/or 5, and/or 6 with one or some (C1-C8)-alkyls; n = 1, 2 or 3, and group or groups of the formula: -CH(OH)-R are at ortho-position and/or at para-position with respect to OH in the cycle group; m = from 0 to 4-n; X means the functional group, such as OH or Hal, or (C1-C8)-alkyl, or (C1-C8)-alkoxyl, or (C5-C12)-aryl comprising in the known cases 1 or 2 heteroatoms, such as nitrogen or oxygen, or carboxy-group, or the group -CO-Y wherein Y means (C1-C8)-alkyl or (C1-C8)-alkoxyl, or amido-group, or amino-group, or thiol-group under condition that at least on of ortho- or para-positions in phenol cycle must be substituted with hydrogen atom, and their salts with alkaline metals, earth-alkaline metals and amines also. Method for preparing indicated phenolic compounds involves interaction of the corresponding substituted phenol wherein at least one ortho- or para-position in phenol cycle must be substituted with hydrogen atom with substituted aldehyde in the presence of a base. Invention provides preparing new compounds that can be used as cross-linking agents no evolving formaldehyde and as intermediate compounds used in organic synthesis.

EFFECT: improved method for preparing.

13 cl, 1 dwg, 10 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of phenols alkylated at ortho-position as parent substances used in preparing organic compounds. Method for preparing o-alkylphenols is carried out by interaction of phenol with alkanol at increased temperature in gaseous phase in the presence of metal oxide as a catalyst. Process is carried out for at least two stages in the molar ratio alkanol : phenol about ≤0.4, preferably, from 0.2 to 0.4 at each stage. Methanol is used as alkanol usually using aluminum gamma-oxide as a catalyst and process is carried out at temperature 300-400°C. Reaction products are separated by distillation. Invention provides increasing yield the end product due to enhancing selectivity with respect to o-alkylphenol.

EFFECT: improved method for preparing.

9 cl, 4 tbl, 2 ex

FIELD: chemical technology.

SUBSTANCE: invention relates to preparing antioxidants of phenolic type. Method involves using alkylation products of mixture of para- and ortho-isomers of isononylphenol with isobutylene as an antioxidant. Alkylation reaction is carried out at 40-120°C and 0.02-0.4 MPa in the presence of acid catalyst in batch and continuous feeding isobutylene to reactor unit providing maintaining isobutylene concentration in reaction mass 0.8 mole/l, not above, and the total amount of isobutylene feeding to alkylation 1.82-2.0 mole per 1 mole parent alkylphenols. Method provides preparing antioxidant showing good technological properties and high effectiveness of protective effect for rubbers of emulsion polymerization and rubbers based on thereof, and simple method for its synthesis also.

EFFECT: improved method for preparing.

6 cl, 3 tbl, 7 ex

The invention relates to a method of selective oxidation of aromatic compounds (e.g. benzene and its derivatives) in gidroksilirovanii aromatic compounds (for example, into the corresponding phenols)

The invention relates to a method of allocation of ALKYLPHENOLS, in particular, para-tert-butylphenol (PTBP) from reaction mixtures

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a new (-)-stereoisomer of formula (I) wherein X is H, or its pharmaceutically acceptable salt which agonise GABA receptor, to a pharmaceutical composition on the basis of the presented compound, to a method for preparing the (-)-stereoisomer of formula (I) or its pharmaceutically acceptable salt, to a method for inducing or maintaining general anaesthesia, to a method for promoting pain management and to a method for promoting pain management and to a method for prototyping antiemetic activity with the use of the presented (-)-stereoisomer or its pharmaceutically acceptable salt, as well as to a new diastereoisomer (-)-2-fluoro-butyl-6-isopropylphenyl ester of carbamic acid of formula (II) wherein R1 represents a chiral amino group, and X is H.

EFFECT: preparing the pharmaceutically acceptable salt which agonise GABA receptor.

16 cl, 12 ex, 6 tbl, 4 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a new (-)-stereoisomer of formula (I) wherein X is H, or its pharmaceutically acceptable salt which agonise GABA receptor, to a pharmaceutical composition on the basis of the presented compound, to a method for preparing the (-)-stereoisomer of formula (I) or its pharmaceutically acceptable salt, to a method for inducing or maintaining general anaesthesia, to a method for promoting pain management and to a method for promoting pain management and to a method for prototyping antiemetic activity with the use of the presented (-)-stereoisomer or its pharmaceutically acceptable salt, as well as to a new diastereoisomer (-)-2-fluoro-butyl-6-isopropylphenyl ester of carbamic acid of formula (II) wherein R1 represents a chiral amino group, and X is H.

EFFECT: preparing the pharmaceutically acceptable salt which agonise GABA receptor.

16 cl, 12 ex, 6 tbl, 4 dwg

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of 2,4,6-trihydroxytoluene (methylphloroglucinol). Method is carried out by hydrolysis of 2,4,6-triaminotoluene salt aqueous solution in acid medium in boiling in the presence of ammonium salt wherein chloride, fluoride, sulfate ammonium are taken as ammonium salt. As 2,4,6-triaminotoluene salt the method involves using hydrochloride or sulfate but sulfate is used preferably. The yield of the end compound is above 75% with the high purity degree. Synthesized compound can be used as a component of compositions used in thermal impregnation and isolation of electric engine winding, for preparing thermostable thermoreactive resins or photosensitive and lithographic plates. Invention provides reducing period of the process and simplifying purification of the end compound.

EFFECT: improved method of synthesis.

3 cl, 2 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to chemistry of chalcone derivatives used in synthesis of biologically active substances, namely to a method for preparing m-phenoxybenzaldehyde-base chalcones of the general formula:

wherein R means hydrogen (H), bromine (Br), chlorine (Cl) atoms, -NO2-group. Method involves interaction of m-phenoxybenzaldehyde with acetophenone or the corresponding substituted acetophenone, i. e.: bromoacetophenone, m-chloroacetophenone and m-nitroacetophenone. The process is carried out in the presence of sodium hydroxide as a catalyst in the mole ratio acetophenone or substituted acetophenone : m-phenoxybenzaldehyde : catalyst = (1.0-1.2):(1.2-1.5):(0.05-0.1), respectively. Mixture of dioxane with methanol taken in the mass ratio = 10:1 is used a solvent, and the process is carried out at room temperature for 20 h followed by isolation of the end product. Invention provides a single-step method with low energy consumption, high yield and purity of end products.

EFFECT: improved preparing method.

4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a new (-)-stereoisomer of formula (I) wherein X is H, or its pharmaceutically acceptable salt which agonise GABA receptor, to a pharmaceutical composition on the basis of the presented compound, to a method for preparing the (-)-stereoisomer of formula (I) or its pharmaceutically acceptable salt, to a method for inducing or maintaining general anaesthesia, to a method for promoting pain management and to a method for promoting pain management and to a method for prototyping antiemetic activity with the use of the presented (-)-stereoisomer or its pharmaceutically acceptable salt, as well as to a new diastereoisomer (-)-2-fluoro-butyl-6-isopropylphenyl ester of carbamic acid of formula (II) wherein R1 represents a chiral amino group, and X is H.

EFFECT: preparing the pharmaceutically acceptable salt which agonise GABA receptor.

16 cl, 12 ex, 6 tbl, 4 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemistry and pharmaceutics, namely an improved method for preparing iodide or methylsulphate neostigmine which can find application as drugs. The method involves preparing sodium 3-dimethylaminophenolate, enabling its reaction with dimethylcarbamoyl acid chloride and reaction of prepared 3-((dimethylcarbomoyloxy)phenyl)-dimethylamine with an alkylating agent (iodomethane or dimethylsulphate). The method is characterised by the fact that target compounds are prepared by the reaction of 3-dimethylaminophenol with 2.0-2.5 molar excess of sodium metal in the toluene medium in boiling, addition of 1.5 molar excess of dimethylcarbamoyl acid chloride, washing out of the toluene filtrate with a sodium alkali solution and water, evaporation of a solvent and keeping of 3-((dimethylcarbomoyloxy)phenyl)-dimethylamine with the relevant alkylating agent for 24 hours in the absolute diethyl ester medium.

EFFECT: method enhancing the 3-dimethylaminophenol conversion, as well as providing higher yield and purity of the end product.

3 ex

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