WO2018014770A1

WO2018014770A1 - Phenol derivative and etomidate pharmaceutical composition, pharmaceutical preparation, and application thereof

Info

Publication number: WO2018014770A1
Application number: PCT/CN2017/092722
Authority: WO
Inventors: 严庞科; 郑伟; 倪佳; 余彦; 莫毅; 陈娅姝
Original assignee: 四川海思科制药有限公司
Priority date: 2016-07-22
Filing date: 2017-07-13
Publication date: 2018-01-25
Also published as: CN112245426A; CN109310676A

Abstract

The present invention relates to a phenol-containing derivative, an etomidate pharmaceutical composition, a preparation method thereof, and application of same in the field of central nervous system treatment. A phenol derivative is a compound represented by formula (I) or a stereoisomer, pharmaceutically acceptable salt, or prodrug thereof.

Description

Pharmaceutical composition, pharmaceutical preparation and use thereof of phenol derivative and etomidate

Technical field

The present invention relates to a pharmaceutical composition of a phenol derivative and etomidate and its use in the field of central nervous system.

Background technique

Propofol can activate a variety of GABA _A receptor subtypes. It is a clinically mature intravenous anesthetic. It is widely used in the induction and maintenance of general anesthesia. It has the advantages of rapid onset and easy to wake up.

However, propofol also has obvious limitations and disadvantages. It has been reported that about 70% of patients have some degree of pain or discomfort when taking propofol (Pascale Picard (2000). Anesthesia & Analgesia, 90, 963-969). Although it has been reported that pretreatment or combination therapy with other drugs can reduce the incidence and severity of propofol injection pain (C.H. Tan et al. (1998). Anaesthesia, 53, 302–305), this pain is still difficult to avoid. The dosage is generally 2.0-2.5 mg/kg, generally used in combination with an analgesic, and the propofol injection for the anesthesia-inducing part can be 0.5 W/V% or 1 W/V% in a ratio of more than 20:1. The lidocaine injection is mixed to reduce the pain of injection.

Propofol has been shown to reduce systolic blood pressure, diastolic blood pressure and mean arterial blood pressure, thus causing hypotension in the clinic. At the same time, respiratory depression is also a risk that cannot be ignored when using propofol. These adverse reactions have largely hampered the use of propofol in a number of clinical cases, such as cardiovascular disease, brain damage and chronic hypotension.

The international patent application WO2014180305 discloses a propofol analog, which is a high-fat soluble substance, which is directly administered into the bloodstream, and can cause rapid onset of anesthesia, especially the compound 1 and other related structures have good anesthetic effects, compounds The structure of 1 is as follows:

Etomidate is a potent and short-acting non-barbital hypnotic intravenous anesthetic with high safety and is one of the commonly used drugs for anesthesia induction. When using regular doses, it’s breathing and The effects of the circulatory system are small and maintain the patient's hemodynamic stability. For patients with malignant hyperthermia, phylloxic disease and pregnant women, it is safer to use Dependent Cool. Can slightly dilate the coronary artery, reduce intracranial pressure and maintain cerebral perfusion, especially for elderly, coronary heart disease, hypertension, shock patients. However, after application of etomidate, side effects such as myoclonus, epileptic-like effects, nausea and vomiting, and inhibition of the synthesis of corpus callosum in the adrenal cortex may occur.

Based on the deficiencies in the prior art, there is a need to provide an intravenous anesthetic having good stability, high efficacy, low dosage, good safety, few side effects, reduced injection pain, good compliance or low cost.

Summary of the invention

The present invention provides a pharmaceutical composition comprising etomidate and a compound of the formula (I) or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, wherein etomidate and a compound of the formula (I) Or the molar ratio of its stereoisomer, pharmaceutically acceptable salt or prodrug is 1:0.01 to 1:15.

Wherein R ¹ and R ² are each independently selected from C _1-4 alkyl or C _3-6 cycloalkyl; n is selected from 1 or 2;

Preferably, R ^{1 is} selected from methyl, ethyl or isopropyl; R ^{2 is} selected from methyl, ethyl, isopropyl or cyclopropyl.

In a preferred embodiment of the invention, the compound of the formula (I) in the pharmaceutical composition is selected from one of the following structures:

or

In a preferred embodiment of the invention, the compound of formula (I) in the pharmaceutical composition is selected from the following structures:

In a preferred embodiment of the present invention, the molar ratio of etomidate to the compound of the formula (I) in the pharmaceutical composition is from 1:0.05 to 1:10, preferably from 1:0.1 to 1:10, further preferably 1: 0.6, 1:1.5, 1:3 or 1:6.

The present invention also provides a pharmaceutical composition comprising etomidate and a compound of the formula (I) or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, the definition of the compound of the formula (I) As defined above,

Wherein the mass ratio of etomidate to the compound of the formula (I) in the pharmaceutical composition is from 1:0.05 to 1:10, preferably from 1:0.1 to 1:10, preferably 1:0.5, 1:1.25, 1: 1.67, 1:2.0, 1:2.5, 1:3.33, 1:5, 1:6.67 or 1:10, more preferably 1:0.5, 1:1.25, 1:2.5 or 1:5.

The present invention relates to a pharmaceutical composition comprising etomidate and a compound of the formula (I) or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, wherein the pharmaceutical composition is the two The medicines are mixed in proportion to a mixed solution and then sold, or distributed in different containers and bundled for sale.

The invention further relates to a pharmaceutical preparation comprising an active ingredient in the pharmaceutical preparation comprising etomidate and a compound of the formula (I) or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, wherein etomidate is The molar ratio of the compound of the formula (I) or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof is from 1:0.05 to 1:10, preferably from 1:0.1 to 1:10, further preferably 1:0.6,1 : 1.5, 1:3 or 1:6; or the mass ratio of etomidate to the compound of the formula (I) is 1:0.05 to 1:10, preferably 1:0.1 to 1:10, further preferably 1:0.5,1 : 1.25, 1:1.67, 1:2.0, 1:2.5, 1:2.5, 1:3.33, 1:5, 1:6.67 or 1:10, still more preferably 1:0.5, 1:1.25, 1:2.5 or 1:5.

Wherein R ¹ and R ² are each independently selected from C _1-4 alkyl or C _3-6 cycloalkyl; n is selected from 1 or 2.

In a preferred embodiment of the invention, the compound of the formula (I) in the pharmaceutical preparation is selected from one of the following structures:

or

Optimal

Compound 1.

In one aspect of the invention, the pharmaceutical preparation is an aqueous preparation comprising:

1) etomidate, the content of which is from 0.01 w/v% to 5 w/v%, preferably from 0.05 w/v% to 3 w/v%, More preferably 0.1w / v% ~ 2w / v%; a compound of the formula (I) or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, in an amount of from 0.01 w / v% to 5 w / v%; Preferably 0.05w/v% to 3w/v%; further preferably 0.1w/v% to 2w/v%;

2) a solubilizer, the content of which is from 0.1 w/v% to 20 w/v%; preferably from 0.1 w/v% to 15 w/v%; further preferably from 0.2 w/v% to 10 w/v%;

3) A latent solvent having a content of from 0 w/v% to w/v 30%; preferably from 0.1 w/v% to 20 w/v%; further preferably from 0.1 w/v% to 10 w/v%.

Preferably, the solubilizing agent is selected from the group consisting of Tween-80, Tween-20, polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, polyethylene glycol 15 hydroxystearate (ie solutol HS15) Or any one or a mixture of any of the poloxamers; preferably Tween-80, Tween-20 or polyethylene glycol 15 hydroxystearate (ie Solutol HS15); The solvent is selected from any one of ethanol, glycerin, propylene glycol or polyethylene glycol or a mixture of any of a few in any ratio.

In another aspect of the invention, the pharmaceutical preparation is a lyophilized preparation comprising:

1) etomidate and a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof;

2) Solubilizer;

3) latent solvent;

4) Filler.

In the preparation of the lyophilized preparation of the present invention, the solution to be lyophilized and to be lyophilized comprises:

1) Etomidate, the content of which is 0.01 w/v% to 5 w/v%, preferably 0.05 w/v% to 3 w/v%, further preferably 0.1 w/v% to 2 w/v%; general formula (I) a compound or a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof, in an amount of from 0.01 w/v% to 5 w/v%; preferably from 0.05 w/v% to 3 w/v%; further preferably from 0.1 to 2 w/ v%;

3) a latent solvent, the content of which is 0 to 30 w/v%; preferably 0.1 w/v% to 20 w/v%; further preferably 0.1 w/v% to 10 w/v%;

4) A filler having a content of from 1 w/v% to 30 w/v%; preferably from 3 w/v% to 15 w/v%; further preferably from 5 w/v% to 10 w/v%.

Preferably, the solubilizing agent is selected from the group consisting of Tween-80, Tween-20, polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, polyethylene glycol 15 hydroxystearate or poloxamer. Any one or any mixture of any ratio; the latent solvent is selected from any one of ethanol, glycerin, propylene glycol or polyethylene glycol or a mixture of any of any ratio; the filler Any one selected from the group consisting of lactose, sucrose, glucose, mannitol, sodium dihydrogen phosphate, sodium phosphate, sodium chloride, disodium hydrogen phosphate, cysteine, glycine, sorbitol, calcium lactobionate, dextran or polyvinylpyrrolidone One or any mixture of any ratio.

In a preferred embodiment of the invention, the lyophilized preparation or aqueous solution preparation further comprises at least one pH adjusting agent in an amount of from 0 to 10 w/v%, preferably from 0 to 5 w/v%.

Preferably, the pH adjusting agent is selected from any one or more of sodium hydroxide, potassium hydroxide, triethanolamine, hydrochloric acid, phosphoric acid, citric acid, acetic acid, malic acid; preferably sodium hydroxide, hydrogen Any one or a mixture of any one of potassium oxide, triethanolamine, phosphoric acid, citric acid, or hydrochloric acid; further preferably one or a mixture of any of sodium hydroxide or hydrochloric acid in any ratio.

In a further preferred embodiment of the invention, the lyophilized formulation or the aqueous solution formulation further comprises at least one isotonicity adjusting agent in an amount of from 0 to 5 w/v%, preferably from 0 to 2 w/v%.

Preferably, the isotonicity adjusting agent is selected from any one of glycerin, a saccharide or a sugar alcohol or a mixture of any one of any ratio; preferably glycerin, glucose, fructose, maltose, polyethylene glycol, Any one or a mixture of any of sorbitol, propylene glycol, xylitol or mannitol in any ratio; more preferably any one or more of glycerin, sorbitol, propylene glycol, polyethylene glycol or mannitol Any mixture of ratios; more preferably any one of glycerin, polyethylene glycol or mannitol or a mixture of any of several ratios; further preferably glycerol.

In still another aspect of the invention, the pharmaceutical preparation is a fat emulsion comprising:

2) Oily ingredients.

Preferably, the oily component is selected to be biocompatible and can be aged in the human body Any one or a mixture of any of the natural or (and) synthetic oils of metabolism; preferably soybean oil, linseed oil, medium chain triglyceride, structural triglyceride, olive oil, corn oil, cottonseed oil Any one or a mixture of any of a mixture of rapeseed oil, peanut oil, safflower oil, coconut oil, castor oil, fish oil, sesame oil or tea oil; preferably soybean oil, olive oil, fish oil, structural triglyceride Any one or a mixture of any of a plurality of fats, linseed oils or medium chain triglycerides; further preferably any one or a mixture of two of soybean oils, medium chain triglycerides, or any ratio of two.

In a preferred embodiment of the invention, the fat emulsion further comprises at least one emulsifier.

Preferably, the emulsifier is selected from the group consisting of glycerol monooleate, Tween-80, Tween-20, poloxamer, polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, polyethylene glycol Glyceride, polyethylene glycol 15 hydroxystearate, egg yolk lecithin, egg yolk phosphatidylcholine, soy lecithin, soybean phosphatidylcholine, hydrogenated egg yolk lecithin, hydrogenated egg yolk phosphatidylcholine, hydrogenated soy lecithin , hydrogenated soybean phosphatidylcholine, dipalmitoyl phosphatidylcholine, dimyristoyl phosphatidylcholine, distearoylphosphatidylcholine, dioleoylphosphatidylcholine, etc. Any of myristic phosphatidylcholine, distearoylphosphatidylglycerol, dipalmitoylphosphatidylethanolamine, docosalylphosphatidylethanolamine, distearoylphosphatidylethanolamine or dioleoylphosphatidylethanolamine Or any mixture of any ratio; further preferably poloxamer, Tween-80, polyethylene glycol 15 hydroxystearate, polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, egg yolk lecithin Or any one or any of soy lecithin Mixture ratio; more preferably a mixture of egg yolk lecithin, soy lecithin any one or two in any ratio.

In a preferred embodiment of the invention, the fat emulsion comprises:

1) Etomidate, the content of which is 0.01 w/v% to 5 w/v%, preferably 0.05 w/v% to 3 w/v%, further preferably 0.1 w/v% to 2 w/v%; general formula (I) a compound or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, in an amount of from 0.01 w/v% to 5 w/v%; preferably from 0.05 w/v% to 3 w/v%; further preferably 0.1 w/v %~2w/v%;

2) an oily component, the content of which is 5 w/v% to 30 w/v%; preferably 5 w/v% to 20 w/v%; further preferably 5 w/v% to 15 w/v%;

3) an emulsifier having a content of 0.5 w/v% to 5 w/v%; preferably 0.5 w/v% to 3 w/v%; The step is preferably from 0.5 w/v% to 2 w/v%.

In a preferred embodiment of the invention, the fat emulsion further comprises at least one co-emulsifier in an amount of from 0 to 0.2 w/v%.

Preferably, the co-emulsifier is selected from the group consisting of sodium oleate, sodium cholate, sodium deoxycholate, oleic acid, cholic acid, deoxycholic acid or cholesterol, or a mixture of any of them in any ratio; Any one or a mixture of two of oleic acid and sodium oleate in any ratio.

In a preferred embodiment of the invention, the fat emulsion further comprises at least one isotonicity adjusting agent in an amount of from 0 w/v% to 5 w/v%.

In a preferred embodiment of the present invention, the fat emulsion further comprises at least one pH adjusting agent in an amount of 0% to 10 w/v%, and the pH adjusting agent is selected from the group consisting of sodium hydroxide, potassium hydroxide, and the like. Any one or any one of ethanolamine, hydrochloric acid, phosphoric acid, phosphate, citric acid, citrate, acetic acid, acetate, malic acid; preferably sodium hydroxide, potassium hydroxide, triethanolamine, or hydrochloric acid Any one or any mixture of any ratio; further preferably one of sodium hydroxide, hydrochloric acid or a mixture of two in any ratio.

In a preferred embodiment of the invention, the fat emulsion comprises:

1) The etomidate content is from 0.1 w/v% to 2 w/v%; the compound of the formula (I) or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, the content of which is 0.1 w/v% 2w/v%;

2) a mixture of any one or two of soybean oil or medium chain triglyceride in an amount of from 5 w/v% to 15 w/v%;

3) egg yolk lecithin, the content of which is 0.5w / v% ~ 2w / v%;

4) glycerin, the content of which is 0w/v% to 5w/v%;

5) sodium oleate, the content of which is 0 to 0.2 w/v%;

In a preferred embodiment of the invention, the pH of the fat emulsion is from 3.0 to 10.0; preferably from 4.0 to 9.0; further preferably 6.0 to 9.0.

In a preferred embodiment of the present invention, the pharmaceutical preparation may further comprise other additives, including but not limited to any one of antioxidants, antibacterial agents, and the like, or a mixture of any of several ratios.

The antibacterial agent includes, but is not limited to, any one or more of methyl benzoate, sodium metabisulfite, disodium edetate, sodium calcium edetate, and the like;

The antioxidants include, but are not limited to, sodium metabisulfite, sodium sulfite, sodium hydrogen sulfite, potassium pyrosulfite, sodium thiosulfate, dibutyl phenol, butylated hydroxyanisole (ie, BHA), tert-butyl-p-benzene. Any one or any of diphenol (TBHQ), dibutylhydroxytoluene (ie, BHT), disodium edetate, or sodium edetate.

The present invention provides a pharmaceutical composition comprising etomidate and a compound of the formula (I) or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof for the preparation of an anesthetic for inducing and maintaining an animal or a human, Use of a pharmaceutical preparation for promoting sedation, hypnosis, treatment and/or prevention of anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions and epilepsy in animals or humans, the active ingredient being etomidate and (I) a compound or a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug.

The invention also provides a method of reducing the side effects of an animal or a human during sedation, induction or maintenance of anesthesia, the method comprising:

Administering to the animal a pharmaceutical composition or a pharmaceutical preparation of the invention; or

The animals are administered a combination of etomidate and a compound of formula (I) in the ratios described herein.

The invention also provides a pharmaceutical composition or a pharmaceutical preparation according to the invention for inducing and maintaining anesthesia of an animal or a human, promoting sedative hypnosis of an animal or a human, treating and/or preventing anxiety, depression, insomnia, Uses of nausea, vomiting, migraine, schizophrenia, convulsions, and epilepsy.

The present invention also provides a combination of etomidate and a compound of the formula (I) or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof for inducing and maintaining anesthesia in an animal or human, promoting sedation in an animal or human Hypnosis, treatment, and/or prevention of anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions, and epilepsy.

Unless otherwise stated, the terms used in the specification and claims have the following meaning.

"w/v%" means the weight of each component (g) / formulation volume (100 mL).

Preparation method of the preparation of the invention

Method 1: Preparation method of fat emulsion

Preparation of oil phase: Weigh the oily component and add the emulsifier, the compound of the formula (I) or its stereoisomer and etomidate to the oily component under high-temperature stirring under an inert gas atmosphere, and stir it evenly as an oil. Phase, control oil phase temperature is 50 ~ 80 °C.

Preparation of the aqueous phase: Under an inert gas atmosphere, the isotonic adjusting agent and the co-emulsifier are added to an appropriate amount of water for injection and stirred uniformly. As an aqueous phase, the temperature of the aqueous phase is controlled to be 50 to 80 °C.

Emulsion preparation: Under an inert gas atmosphere, the oil phase is slowly added to the aqueous phase to obtain colostrum under high-speed agitation, and the colostrum preparation can be carried out at 50-80 °C. The mixture is repeatedly homogenized by a high-pressure homogenizer until the milk particles are qualified, filtered, potted, sterilized, and cooled to obtain a milky injection of the compound of the formula (I) and etomidate.

The pH of the fat emulsion of the present invention is achieved by adjusting the pH of the aqueous phase, and the pH of the finished product is lower than the pH value of the aqueous phase; the pH of the finished product is usually adjusted to 3.0-10.0, preferably, the pH is 4.0 to 9.0, more preferably The pH is from 6.0 to 9.0. In the preparation method, the stirring mode, the rotation speed and the time are controlled as needed, and the high-shear mixing emulsifier is preferred in the preparation of the colostrum. This selection can be carried out as needed. When the high-pressure homogenizer is homogenized, the conditions and time of homogenization are well known to those skilled in the art, as long as the average particle size of the homogenized milk particles does not exceed 350 nm, and the particle size of 95% of the particles must not exceed 1.5 μm. There are particles having a particle size larger than 5 μm. The sterilization may be by autoclaving, hot water immersion sterilization, spray sterilization, etc., as an example of a more preferred sterilization process, which may be sterilized by autoclaving (for example, 121 ° C, 12 minutes).

In the fat emulsion preparation method of the present invention, the inert gas is selected from, but not limited to, nitrogen.

The invention relates to a method for preparing a fat emulsion, which comprises the compound of the formula (I) or a stereoisomer thereof and etomidate dispersed uniformly in an injectable oil and an emulsifier and encapsulated by an oil phase, and then added to an aqueous phase. The oil-in-water fat emulsion has good stability and small clinical side reactions. The accelerated and long-term stability test proves that the quality of the product is stable and is favorable for large-scale production.

Method 2: Preparation method of aqueous solution preparation

As long as a clear liquid preparation can be obtained, the method of mixing the ingredients is not limited and can be The general process is carried out. For example: weigh the compound of the formula (I) or its stereoisomer, pharmaceutically acceptable salt or prodrug and etomidate, solubilizer, control temperature of 20 ~ 80 ° C, stir evenly, to obtain a mixed solution (1 ); weigh the isotonic regulator, add 50% ~ 80% of the total preparation amount of water for injection and stir to obtain a mixed solution (2), the latent solvent and other additives can be added to (1) or (2) according to the situation, Mixing (1) and (2) with stirring, stirring to obtain a clear liquid; adding appropriate amount of needle to the activated carbon, stirring and adsorbing for 5 to 30 minutes, decarbonizing, and adjusting the pH to 3.0-10.0 with a pH adjuster, preferably, The pH is 4.0 to 9.0, more preferably, the pH is 6.0 to 9.0, water for injection is added to the preparation volume, and the mixture is uniformly stirred; the 0.22 μm filter element is filtered and potted; and autoclaved to obtain an aqueous solution preparation.

Method 3: Preparation method of lyophilized preparation

As long as a qualified lyophilized preparation can be obtained, the solution preparation and lyophilization process before lyophilization are not limited, and can be carried out according to a general process. For example: weigh the compound of the formula (I) or its stereoisomer, pharmaceutically acceptable salt or prodrug and etomidate, solubilizer, control temperature of 20 ~ 80 ° C, stir evenly, to obtain a mixed solution (1 ). Weigh the isotonic regulator and filler, add 50~ 80% of the total preparation amount of water for injection and stir to obtain the mixed solution (2). The latent solvent and other additives can be added to (1) or (2) according to the situation. (1) and (2) are mixed under stirring, and the mixture is uniformly stirred to obtain a clear liquid. Adding appropriate amount of needle to activated carbon, stirring and adsorbing for 5 to 30 minutes, decarbonizing, and adjusting the pH to 3.0-10.0 with a pH adjuster, preferably, the pH is 4.0 to 9.0, more preferably, the pH is 6.0 to 9.0, and water for injection is added. To the preparation volume, stir evenly. The 0.22 μm filter was filtered. Filled in a vial according to the specified amount, half-plugged, and pre-freeze in the front box of the freeze dryer. Freeze-dried. Vacuum or fill with a suitable amount of inert gas plug, out of the box and roll.

The preparation method of the lyophilized preparation used in the invention has the remarkable feature that the preparation method is simple and convenient, is more convenient for long-term storage and convenient transportation, and is advantageous for large-scale production.

DRAWINGS

Figure 1 is a test result of rat adrenal function in Test Example 2 (* compared with blank fat emulsion, P < 0.05).

detailed description

The embodiments of the present invention and the beneficial effects thereof are described in detail below by way of specific examples, which are intended to provide a better understanding of the nature and characteristics of the present invention.

The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is given in units of 10 ^-6 (ppm). The NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD). ), the internal standard is tetramethylsilane (TMS);

For the determination of MS (Agilent 6120B (ESI) and Agilent 6120B (APCI));

HPLC was determined using an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18100 x 4.6 mm, 3.5 μM);

Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate. The specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm~0.20mm. The specification for thin layer chromatography separation and purification is 0.4mm. ~0.5mm;

Column chromatography generally uses Yantai Yellow Sea silica gel 200 ~ 300 mesh silica gel as a carrier;

The known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from Titan Technology, An Naiji Chemical, Shanghai Demo, Chengdu Kelon Chemical, Suiyuan Chemical Technology, Belling Technology, etc. The company, in which etomidate was purchased from Chengdu Dangdang Times Pharmaceutical Technology Co., Ltd., Compound 1 was supplied by Sichuan Haisike Pharmaceutical Co., Ltd., and the product was purchased from yimimide emulsion injection. The manufacturer was Jiangsu Enhua Pharmaceutical Co., Ltd., phenol derivative. Synthesis and preparation of preparations reference WO2014180305 and WO2016034079;

The nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon of about 1 L volume;

The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume;

The hydrogenation reaction is usually evacuated, filled with hydrogen, and operated three times;

Unless otherwise stated in the examples, the reaction is carried out under a nitrogen atmosphere;

There is no special description in the examples, and the solution means an aqueous solution;

There is no special description in the examples, the reaction temperature is room temperature, the optimum reaction temperature at room temperature, It is 20 ° C ~ 30 ° C.

Example 1 Preparation of Fat Emulsion

prescription:

Under the protection of nitrogen, weigh the injection soybean oil [source: AVIC (Tieling) Pharmaceutical Co., Ltd.], medium chain triglyceride [source: AVIC (Tieling) Pharmaceutical Co., Ltd.], and heat to about 50 ° C. Add high-quality stirring to add egg yolk lecithin (source: Lipip GmbH, Germany), compound 1, etomidate, stir evenly, control temperature is 55-75 ° C as oil phase; glycerin for injection (Source: Hunan Erkang Pharmaceutical Co., Ltd.) Company), sodium oleate is added to the appropriate amount of water for injection, mixed and adjusted to the appropriate range with the pH of the aqueous phase with sodium hydroxide (to ensure the pH of the finished product is 6.0 to 9.0), and the control temperature is 55 to 75 ° C as the aqueous phase. The emulsified milk phase was added to the aqueous phase under high-speed agitation (high shear mixing emulsifier, IKA production) to prepare colostrum, and the colostrum preparation was carried out at 55 to 75 °C. After repeated homogenization by high-pressure homogenizer (GEA Niro production), after checking the milk particles to meet the requirements, the emulsion is filtered and sterilized by nitrogen, sterilized in a steam sterilizer, cooled, and the compound 1 or etomidate is obtained after passing the test. Milky injection.

Example 2 Preparation of Fat Emulsion

prescription:

Under the protection of nitrogen, weigh the injection soybean oil [source: AVIC (Tieling) Pharmaceutical Co., Ltd.], medium chain triglyceride [source: AVIC (Tieling) Pharmaceutical Co., Ltd.], and heat to about 50 ° C. Add high-quality stirring to add egg yolk lecithin (source: Lipip GmbH, Germany), compound 1, etomidate, stir evenly, control temperature is 55-75 ° C as oil phase; glycerin for injection (Source: Hunan Erkang Pharmaceutical Co., Ltd.) Company), sodium oleate is added to the appropriate amount of water for injection, mixed and adjusted to the appropriate range with the pH of the aqueous phase with sodium hydroxide (to ensure the pH of the finished product is 6.0 to 9.0), and the control temperature is 55 to 75 ° C as the aqueous phase. The emulsified milk phase was added to the aqueous phase under high-speed agitation (high shear mixing emulsifier, IKA) to prepare colostrum, and the colostrum preparation was carried out at 55 to 75 °C. After repeated homogenization by high-pressure homogenizer, after checking the milk particles to meet the requirements, the emulsion is filtered and sterilized by nitrogen, sterilized in a steam sterilizer, cooled, and the compound 1 / etomidate emulsion injection is obtained after passing the test.

Other ratios of fat emulsions of Compound 1 + etomidate can be prepared by reference to Example 1 or 2.

Example 3 Preparation of Fat Emulsion

prescription:

Under the protection of nitrogen, weigh the injection soybean oil [source: AVIC (Tieling) Pharmaceutical Co., Ltd.], medium chain triglyceride [source: AVIC (Tieling) Pharmaceutical Co., Ltd.], and heat to about 50 ° C. Add high-quality stirring to add egg yolk lecithin (source: Lipip GmbH, Germany), compound 1, stir evenly, control temperature is 55-75 ° C as oil phase; glycerin for injection (source: Hunan Erkang Pharmaceutical Co., Ltd.), oil Sodium is added to an appropriate amount of water for injection, mixed and adjusted to a suitable pH range (to ensure a finished product pH of 6.0 to 9.0), and a controlled temperature of 55 to 75 ° C as an aqueous phase. The emulsified milk phase was added to the aqueous phase under high-speed agitation (high shear mixing emulsifier, IKA production) to prepare colostrum, and the colostrum preparation was carried out at 55 to 75 °C. It is repeatedly homogenized by high-pressure homogenizer (produced by GEA Niro). The emulsion is inspected to meet the requirements. After the emulsion is filtered, it is sealed with nitrogen, sterilized in a steam sterilizer, cooled, and the emulsion of Compound 1 is obtained after passing the test.

Other levels of fat emulsion of Compound 1 can be prepared by reference to Example 3.

Biological test case

Test Example 1: Canine efficacy test of different doses of Compound 1 in combination with etomidate

Beagle (Chengdu Dashuo Biotechnology Co., Ltd.), 8-9kg, 6 females, half male and half female. Beagle dogs were fasted for 16 hours before administration. On the day of administration, a single intravenous injection of etomidate emulsion (Jiangsu Enhua Pharmaceutical Co., Ltd.) and a mixture of compound 1 and etomidate at different doses were used to record the induction time of beagle anesthesia. Time, while observing Beagle tendon and nausea and vomiting. The experimental results are shown in Table 1:

Anesthesia induction time: the time from the administration to the disappearance of righting reflex;

Duration of anesthesia: the time when the righting reflex disappears until the righting reflex is restored;

Table 1 Dog efficacy test of compound 1 combined with etomidate

Conclusion: When etomidate alone, the duration of anesthesia increased with the dose of etomidate, and the incidence of adverse reactions such as tendon and nausea and vomiting increased. After the combination of different doses of compound 1, the induction time of anesthesia was shortened. The duration of anesthesia was prolonged, and no adverse reactions such as tendon and nausea and vomiting were observed.

When Compound 1 is combined with etomidate, it not only achieves the anesthetic effect when used alone, but also significantly improves the adverse reactions when etomidate is used alone, improves the safety of the drug and improves the patient experience.

Test Example 2. Detection of rat adrenal function

SPF grade SD rats, 250-300 g, male, were provided by Beijing Vital Lihua. Before the experiment, the animals were fasted and water was not allowed. On the next day, all animals were randomly divided into 4 groups according to body weight. Each group of animals received intravenous dexamethasone 0.2 mg/kg, and 200 μl of blood was collected from the jugular sinus 2 h after injection. After blood collection, intravenous administration, intravenous injection of dexamethasone sodium phosphate injection 0.2mg/kg, test compound (blank fat emulsion or compound 1 or etomidate or compound 1 combined with etomidate) and adrenal cortex The N-terminal 24 peptide of hormone (ACTH (1-24)) 25 μg/kg; 200 μl of blood was collected from the jugular sinus 15 min after injection and 30 min after injection. The dosing schedule is shown in Table 2 below. After the whole blood collected twice was coagulated at room temperature for 30 min, the supernatant was collected and stored at -80 ° C. The serum corticosterone concentration was determined by enzyme-linked immunosorbent assay (ELISA). The results of rat adrenal function test are shown in Figure 1. .

Table 2 Rat adrenal cortical function test drug dosage regimen

名称name	给药剂量Dosage	动物数量Number of animals
空白脂肪乳Blank fat milk	10ml/kg10ml/kg	88
化合物1Compound 1	2.5mg/kg2.5mg/kg	88
依托米酯Estradiol	2mg/kg2mg/kg	88
化合物1+依托米酯Compound 1 + etomidate	1.25mg/kg+1mg/kg1.25mg/kg+1mg/kg	88

Conclusion: The etomidate alone can significantly inhibit the adrenal cortex function in rats at the dose of 2 mg/kg, and the combination of compound 1 with etomidate can significantly improve the inhibitory effect of etomidate on renal cortical function.

Test Example 3 Study on the Safety of Combination of Compound 1 and Etomidate

Test purposes:

The safety of anesthesia induction was evaluated by a single dose of a combination of Compound 1 and etomidate.

Test plan:

The test was an open label, and a single dose of Compound 1 and etomidate was administered intravenously to the subject to evaluate the anesthesia/sedation effect and safety.

Adult healthy male subjects were selected and the subjects were randomly divided into 4 groups (control group, test group 1, test group 2, test group 3), with 5 persons in each group. The doses administered in each group are as follows:

Control group: 0.648 mg / kg of compound 1;

Test group 1: a combination of 0.324 mg/kg of compound 1 and 0.15 mg/kg of etomidate,

Test group 2: a combination of 0.216 mg/kg of Compound 1 and 0.20 mg/kg of etomidate,

Test group 3: a combination of 0.432 mg/kg of Compound 1 and 0.10 mg/kg of etomidate.

The above doses were administered such that the control group, the test group 1, the test group 2, and the test group 3 were able to achieve the same depth of anesthesia.

Mode of administration and route: Each group of subjects will be administered intravenously according to the above-mentioned administration dose, wherein the combination of Compound 1 and etomidate in Test Groups 1, 2, and 3 is a pre-compound containing Compound 1 and etomidate. Mixed injections. Use the infusion pump to take the medicine in more than 60 seconds The injection is intravenously administered to the subject's elbow fossa. From the first night of the trial to the morning of the second day, all subjects will be in the study room, then leave the study room and ask the subject to return on day 7. The test results are shown in Tables 3, 4, and 5.

Table 3 anesthesia effect of each group

Table 4 Comparison of blood pressure before and after administration in the control group

Note: The baseline value is the last reliable value obtained before administration (-15 min, -10 min, -5 min, 0 min), typically 0 min. Here, the baseline values are calculated in two ways, namely

*: t = 0 min; △: t = -15 min, t = -10 min, t = -5 min mean

SBP: systolic blood pressure; DBP: diastolic blood pressure

Table 5 Comparison of blood pressure before and after administration in the test group 1, 2, and 3

Conclusion: In the case of the same depth of anesthesia (equivalent), the combination of the two drugs makes the patient's blood pressure more stable and side effects may be less.

Claims

A pharmaceutical composition comprising etomidate and a compound of the formula (I) or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, characterized by etomidate and a compound of the formula (I) or The molar ratio of the stereoisomer, pharmaceutically acceptable salt or prodrug thereof is from 1:0.01 to 1:15.

Wherein R 1 and R 2 are each independently selected from C 1-4 alkyl or C 3-6 cycloalkyl; n is selected from 1 or 2.
The pharmaceutical composition according to claim 1, wherein:

R 1 is selected from methyl, ethyl or isopropyl; and R 2 is selected from methyl, ethyl, isopropyl or cyclopropyl.
The pharmaceutical composition according to claim 2, wherein the compound of the formula (I) is selected from one of the following structures:
The pharmaceutical composition according to any one of claims 1 to 3, wherein the molar ratio of etomidate to the compound of the formula (I) or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof is 1 0.05 to 1:10, preferably 1:0.1 to 1:10, more preferably 1:0.6, 1:1.5, 1:3 or 1:6.
A pharmaceutical composition comprising etomidate and a compound of the formula (I) or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, the compound of the formula (I) being as defined in claim 3 Consistent,

It is characterized in that the mass ratio of etomidate to the compound of the formula (I) is 1:0.05 to 1:15, preferably 1:0.5 to 1:10, more preferably 1:0.5, 1:1.25, 1:1.67, 1: 2.0, 1:2.5, 1:2.5, 1:3.33, 1:5, 1:6.67 or 1:10.
A pharmaceutical preparation comprising an active ingredient comprising etomidate and a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, wherein etomidate is The molar ratio of the compound of the formula (I) or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof is from 1:0.05 to 1:10;

Wherein R 1 and R 2 are each independently selected from C 1-4 alkyl or C 3-6 cycloalkyl; n is selected from 1 or 2.
The pharmaceutical preparation according to claim 6, wherein

R 1 is selected from methyl, ethyl or isopropyl; and R 2 is selected from methyl, ethyl, isopropyl or cyclopropyl.
The pharmaceutical preparation according to claim 7, characterized in that the definition of the compound of the formula (I) is in accordance with claim 3.
A pharmaceutical preparation comprising an active ingredient comprising etomidate and a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, comprising 0.01 w/ v% ~ 5w / v% of etomidate, 0.01w / v% ~ 5w / v% of the compound of the general formula (I)

The definition of the compound of the formula (I) is in accordance with claim 3.
Pharmaceutical preparation according to any one of claims 6 to 9, characterized in that the medicine The preparation is an aqueous solution preparation, a lyophilized preparation or a fat emulsion.
The pharmaceutical preparation according to claim 9, wherein the pharmaceutical preparation is an aqueous preparation containing 0.01w/v% to 5w/v% of etomidate, and 0.01w/v% to 5w/v% of the passage. a compound of formula (I), a solubilizer of from 0.1 w/v% to 20 w/v%, and a latent solvent of from 0 to 30 w/v%.
The pharmaceutical preparation according to claim 11, wherein the aqueous solution preparation comprises 0.05 w/v% to 3 w/v% of etomidate, 0.05 w/v% to 3 w/v% of the compound of the formula (I) a solubilizing agent of 0.1 w/v% to 15 w/v%, and a latent solvent of 0.1 w/v% to 20 w/v%, preferably, the aqueous solution preparation comprises 0.1 w/v% to 2 w/v% of etomi. Ester, 0.1 w/v% to 2 w/v% of the compound of the formula (I), 0.2 w/v% to 10 w/v% of a solubilizer, and 0.1 w/v% to 10 w/v% of a latent solvent.
The pharmaceutical preparation according to claim 11 or 12, wherein:

The solubilizing agent is selected from the group consisting of Tween-80, Tween-20, polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, polyethylene glycol 15 hydroxystearate or poloxamer. One or any mixture of any ratio;

The latent solvent is selected from any one of ethanol, glycerin, propylene glycol or polyethylene glycol or a mixture of any of a few in any ratio.
The pharmaceutical preparation according to claim 9, wherein the pharmaceutical preparation is a lyophilized preparation, and the solution to be lyophilized is contained in a solution of 0.01w/v% to 5w/v% of etomidate, 0.01. w/v% to 5w/v% of the compound of the formula (I), 0.1w/v% to 20w/v% of a solubilizer, 0 to 30 w/v% of a latent solvent, and 1 w/v% to 30 w/v% Filler.
The pharmaceutical preparation according to claim 14, wherein the solution to be lyophilized and the solution to be lyophilized comprises 0.05w/v% to 3w/v% of etomidate, and 0.05w/v% to 3w/v% of the solution. a compound of the formula (I), a solubilizer of from 0.1 w/v% to 15 w/v%, a latent solvent of from 0.1 w/v% to 20 w/v%, and a filler of from 3 w/v% to 15 w/v%, preferably, The solution to be lyophilized after completion of the solution comprises 0.1 w/v% to 2 w/v% of etomidate, 0.1 w/v% to 2 w/v% of the compound of the formula (I), and 0.2 w/v%. 10 w/v% solubilizer, 0.1 w/v% to 10 w/v% of latent solvent and 5 w/v% to 10 w/v% of filler.
The pharmaceutical preparation according to claim 14 or 15, wherein:

The solubilizing agent is selected from the group consisting of Tween-80, Tween-20, polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, polyethylene glycol 15 hydroxystearate or poloxamer. One or any mixture of any ratio;

The latent solvent is selected from any one of ethanol, glycerin, propylene glycol or polyethylene glycol or a mixture of any of several ratios;

The filler is selected from the group consisting of lactose, sucrose, glucose, mannitol, sodium dihydrogen phosphate, sodium phosphate, sodium chloride, disodium hydrogen phosphate, cysteine, glycine, sorbitol, calcium lactate, dextran or poly Any one or a mixture of any of several vinylpyrrolidone in any ratio.
The pharmaceutical preparation according to any one of claims 11 to 16, characterized in that the aqueous solution preparation or the lyophilized preparation further comprises 0 w/v% to 10 w/v% of a pH adjuster, respectively.
The pharmaceutical preparation according to claim 17, wherein said pH adjusting agent is selected from any one of sodium hydroxide, potassium hydroxide, triethanolamine, hydrochloric acid, citric acid or phosphoric acid or any ratio of any one of them. mixture.
The pharmaceutical preparation according to any one of claims 11 to 18, characterized in that the aqueous solution preparation or the lyophilized preparation further comprises 0 to 5 w/v% of an isotonicity adjusting agent, respectively.
The pharmaceutical preparation according to claim 19, wherein the isotonicity adjusting agent is selected from any one or a mixture of any one of glycerin, sorbitol, propylene glycol, polyethylene glycol or mannitol.
The pharmaceutical preparation according to claim 9, wherein the pharmaceutical preparation is a fat emulsion comprising 0.01w/v% to 5w/v% of etomidate, and 0.01w/v% to 5w/v% of the passage. A compound of formula (I), an oily component of from 5 w/v% to 30 w/v%, and an emulsifier of from 0.5 w/v% to 5 w/v%.
The pharmaceutical preparation according to claim 21, wherein the fat emulsion comprises 0.05 w/v% to 3 w/v% of etomidate, 0.05 w/v% to 3 w/v% of the compound of the formula (I) 5w/v% to 20w/v% of an oily component and 0.5w/v% to 3w/v% of an emulsifier, preferably, the fat emulsion comprises 0.1w/v% to 2w/v% of etomidate 0.1w/v% to 2w/v% of the compound of the formula (I), 5w/v% to 15w/v% of the oil component, and 0.5w/v% to 2w/v% of the emulsifier.
The pharmaceutical preparation according to claim 21 or 22, wherein:

The oily component is selected from the group consisting of soybean oil, olive oil, fish oil, linseed oil, medium chain triglyceride, structural triglyceride or a mixture of any of several ratios;

The emulsifier is selected from the group consisting of poloxamer, Tween-80, polyethylene glycol 15 hydroxystearate, polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, egg yolk lecithin or soy lecithin Any one or any mixture of any ratios.
The pharmaceutical preparation according to any one of claims 21 to 23, characterized in that the fat emulsion further comprises 0 to 0.2 w/v% of a co-emulsifier.
The pharmaceutical preparation according to claim 24, wherein the co-emulsifier is selected from any one or a mixture of two of oleic acid and sodium oleate.
The pharmaceutical preparation according to any one of claims 21 to 25, wherein the fat emulsion further comprises 0 to 5 w/v% of an isotonicity adjusting agent.
The pharmaceutical preparation according to claim 26, wherein the isotonicity adjusting agent is selected from any one or a mixture of any one of glycerin, sorbitol, propylene glycol, polyethylene glycol or mannitol.
The pharmaceutical preparation according to claim 27, characterized in that the fat emulsion comprises 0.1 w/v% to 2 w/v% of etomidate, 0.1 w/v% to 2 w/v% of the compound of the formula (I) Any one or a mixture of 5w/v% to 15w/v% of soybean oil or medium chain triglyceride, 0.5w/v% to 2w/v% of egg yolk lecithin, 0w/ V% to 5 w/v% glycerol and 0 to 0.2 w/v% sodium oleate.
The pharmaceutical preparation according to claim 28, wherein the fat emulsion has a pH of from 3.0 to 10.0, preferably, a pH of from 4.0 to 9.0, more preferably, a pH of from 6.0 to 9.0.
A pharmaceutical composition according to any one of claims 1 to 5, which is useful for inducing and maintaining anesthesia in an animal or human, promoting sedative hypnosis in an animal or human, treating and/or preventing anxiety, depression, insomnia, nausea, Use in medicines for vomiting, migraine, schizophrenia, convulsions, and epilepsy.
A method of reducing the side effects of an animal or human being during sedation, induction or maintenance of anesthesia, the method comprising:

The pharmaceutical composition according to any one of claims 1 to 5, or the pharmaceutical preparation according to any one of claims 6 to 29, which is administered to a human or an animal; or

Administration of etomidate and a compound of formula (I) in a ratio according to any one of claims 1 to 5 in combination with humans or animals.
A pharmaceutical composition according to any one of claims 1 to 5, or a pharmaceutical preparation according to any one of claims 6 to 29 for inducing and maintaining anesthesia in an animal or a human, promoting sedation and hypnosis in an animal or a human, Treat and/or prevent anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions, and epilepsy.
Etomidate and a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof are administered in combination for inducing and maintaining anesthesia in an animal or human, promoting sedation, hypnosis, treatment and / or prevent anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions and epilepsy,

Wherein R 1 and R 2 are each independently selected from C 1-4 alkyl or C 3-6 cycloalkyl; n is selected from 1 or 2.
A pharmaceutical composition comprising etomidate and a compound of the formula (I) or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, characterized by a formulation according to any one of claims 1 to 5 In contrast, the two drugs are mixed in proportion to a mixed solution, or are dispensed in different containers in proportion.