阅读说明：本技术 一类卤代咪唑类化合物、制备方法及用途 (Halogenated imidazole compounds, preparation method and application ) 是由 杨亮 于 2018-07-01 设计创作，主要内容包括：本发明公开了一类卤代咪唑类化合物、制备方法及用途,其结构为<Image he="248" wi="435" file="DDA0001715283930000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>式中的C*为R型手性碳,R<Sub>1</Sub>和R<Sub>2</Sub>可独立选自H、C1～6的烷基；R<Sub>3</Sub>为取代或非取代的C<Sub>1～18</Sub>饱和或不饱和的脂肪族烃,其中脂肪族烃包括直链、支链或环状脂肪族烃基；X为H或卤原子；Y为H或卤原子；X与Y不能同时为H。该类化合物或其药学上可接受的盐或溶剂化物,几乎没有皮质激素抑制作用,同时可以产生快速可逆的麻醉效应,并可快速代谢为无活性的羧酸代谢物,停药后的苏醒质量好；单次给药或持续给药后机体的皮质激素功能都能迅速恢复,用药后肌肉震颤的发生率低且停药后迅速苏醒。该类化合物或其盐类化合物可用于制备对人或动物产生镇静催眠和/或麻醉作用的中枢抑制性药物。(The invention discloses a halogenated imidazole compound, a preparation method and application thereof, and the structure is Wherein C is R type chiral carbon, R 1 And R 2 Alkyl groups which can be independently selected from H, C1-6; r 3 Is substituted or unsubstituted C 1～18 Saturated or unsaturated aliphatic hydrocarbons, wherein aliphatic hydrocarbons include straight, branched, or cyclic aliphatic hydrocarbon groups; x is H or a halogen atom; y is H or a halogen atom; x and Y cannot be H at the same time. The compound or the pharmaceutically acceptable salt or solvate thereof has almost no corticoid inhibition effect, and simultaneously canThe compound has quick and reversible anesthetic effect, can be quickly metabolized into inactive carboxylic acid metabolites, and has good reviving quality after stopping the drug; the cortical hormone function of the body can be quickly recovered after single administration or continuous administration, the incidence rate of muscle tremor after administration is low, and the body can be quickly recovered after stopping administration. The compounds or their salts can be used for preparing centrally inhibitory drugs for producing sedative-hypnotic and/or anesthetic effects on human or animals.)

1. The halogenated imidazole compound is characterized by having a structure shown as a formula (I)

C in formula (I) is R type chiral carbon, R₁And R₂Can be independently selected from H, methyl, ethyl, cyclopropyl, cyclobutyl or isopropyl, or R₁And R₂Form C_2～5A support base of (1); r₃Is substituted or unsubstituted C_1～18Saturated or unsaturated aliphatic hydrocarbons, including straight, branched or cyclic aliphatic hydrocarbon groups; x is H or a halogen atom; y is H or a halogen atom; x and Y cannot be H at the same time.

2. The halogenated imidazoles as claimed in claim 1 characterized by: r1 ═ H; r2 ═ H, CH3, CH2CH 3; r3 is C1-8 alkyl; x ═ H, F, Cl, Br; y ═ H, F, Cl, Br; x and Y cannot be H simultaneously; representative compounds are:

3. the halogenated imidazole compound according to any one of claims 1 to 3, wherein the pharmaceutically acceptable salt compound of the compound having the structure of formula (I) is a sulfonate, a hydrobromide, a sulfate hydrochloride or a tartrate of the compound having the structure of formula (I).

4. A halogenated imidazole compound according to any one of claims 1 to 3 characterised in that it is a solvate, such as a hydrate, of a compound of formula (i).

5. A process for the preparation of halogenated imidazoles as claimed in any one of claims 1 to 3, characterized in that the target compound of formula (i) is obtained by substitution of an N-substituted imidazolecarboxylic acid compound of formula (ii) with a halide of formula (iii), by the following reaction sequence:

r in the structure of the reactant₁、R₂、R₃X and Y are as defined in claim 1.

6. A method for preparing halogenated imidazoles as claimed in claims 1 to 3, characterized in that the silver salt of the compound (ii) is prepared first and then reacted with the compound (iii) to obtain the target product, the reaction process is as follows:

7. the halogenated imidazole compound according to any one of claims 1 to 4, wherein the halogenated imidazole compound, the optical isomer thereof, the pharmaceutically acceptable salt compound thereof, the solvent compound thereof, the preparation formed by the above substances or the pharmaceutical composition thereof is used for preparing a central inhibitory drug which has sedative-hypnotic and/or anesthetic effects on humans or animals.

Technical Field

The invention relates to a halogenated imidazole compound which has no corticoid inhibition and has the characteristics of short-acting anesthesia and quick recovery after drug withdrawal, a preparation method and application thereof.

Background

Etomidate is a hypnotic general anesthetic drug for veins, is a derivative with an imidazole structure, has the advantage of high safety, and is one of common drugs for surgical anesthesia induction. Etomidate has been clinically applied for nearly 30 years, and is an ideal general anesthetic due to high onset speed and moderate anesthesia maintenance time. Etomidate has effects of anesthesia, central tranquilization hypnosis and amnesia, and has no effects of relieving pain and relaxing muscle. The pharmacological action of etomidate is mainly related to GABA of central nerve_AReceptor-related hypnotic effects associated with GABA_AThe receptor has a greater relationship between the β 2 and β 3 subunits than the α 1 subunit. GABA_AReceptor antagonists are effective in antagonizing the central nervous effects of etomidate. When the etomidate acts, the sensitivity of the receptor to inhibitory neurotransmitter GABA is greatly improved through the combination with the receptor, so that the anesthetic and sedative effects are generated. Etomidate has a therapeutic index (LD50/ED50) of 26.4, a large safe dose range, and little effect on cardiovascular function. Under the clinical routine dosage, the heart rate, the mean arterial pressure, the mean pulmonary arterial pressure, the pulmonary capillary wedge pressure, the central venous pressure, the stroke volume of the heart, the cardiac index, the pulmonary vascular resistance and the peripheral vascular resistance of patients and ordinary patients with heart diseases hardly change, and the hemodynamic stability of the compound is related to that etomidate does not influence the function of a baroreceptor, does not influence the function of peripheral vascular relaxation and does not inhibit the myocardial contractility. Therefore, etomidate is considered to be more suitable for elderly and patients with cardiac insufficiency (Bovill JG.2006; Passot Set al.2005). Meanwhile, etomidate has little influence on the respiratory system, including spontaneous respiration, ventilation capacity and airway responsiveness. Therefore, the use of etomidate anesthesia is more favorable for maintaining spontaneous breathing, and no histamine release phenomenon is observed even when etomidate is applied to patients with airway hyperreactivity.

The adrenocortical hormone inhibitory action of etomidate is of concern, greatly limiting its clinical use as an anesthetic and sedative. Etomidate, especially a prolonged continuous use of etomidate, significantly inhibits the synthesis of corticosteroids in patients. The clinical application shows that etomidate can obviously reduce the level of plasma corticoid, and the single use can continuously inhibit for 6 to 8 hours, so that adrenal cortex can lose normal response to adrenocorticotropic hormone (ACTH). The synthesis of corticoids in patients is an important mechanism for resisting inflammation in the body, so that the characteristic of etomidate is unfavorable for patients, especially critical patients such as intensive care patients, sepsis patients and trauma patients, and even leads to higher mortality of the patients (WattI and Ledingham IM.1984; McKee JI and Finlay WE.1983; Albert SG et al 2011).

Therefore, the novel anesthetic for reducing the inhibition of the adrenocortical hormone is developed on the basis of etomidate, and the novel anesthetic has important clinical application value. Etomidate molecules are modified through a soft drug design idea, so that the in-vivo metabolic rate of the drug is improved, the blood level of a patient is quickly reduced, and the inhibition on the cortical hormone level of the patient can be greatly improved. Methoxycarbonyletomidate MOC-ET (chinese patent CN 102046607a) combines a diester bond with the ester bond of existing etomidate to form a new soft drug which can be metabolized rapidly. The effect of MOC-ET for regulating GABA receptors is similar to that of etomidate, the MOC-ET can be quickly metabolized by nonspecific esterase in blood and tissues, the half-life period is several minutes, the MOC-ET can be quickly metabolized, but the metabolite generated after the drug is metabolized in vivo also has considerable corticoid and central inhibition activity, so that the patient has poor postoperative recovery quality, and the inhibition of the corticoid of the patient is not obviously reduced (Ge RL ET al 2012; Pejo E ET al 2012); furthermore, MOC-ET is poorly druggable as it has only one-fifth the potency of etomidate at animal level (j.f. cotton ET al.2009). On the basis of the CPMM, the second generation soft medicine is continuously developed. Although the potency of the drug is close to that of etomidate, and the drug can quickly recover after being stopped, and the drug has a faster in vivo metabolic rate, the drug still has an obvious inhibitory effect on the corticoids of patients in the process of continuously infusing the drug (Campagna JA et al 2014), and the quality of the drug after recovery from anesthesia can be obviously influenced. During use, a higher incidence of muscle tremor was also observed at the animal level, which is detrimental to patient stability during surgery. In addition, a class of halogen-containing derivatives has been developed by modifying the structure of etomidate. The developed derivatives partially improve the inhibition of the synthesis function of the corticoid, but the recovery rate after continuous administration is not improved significantly (WO 2017059827).

Therefore, no novel etomidate narcotic drug that does not inhibit corticoid function during sustained use and that can rapidly recover after administration has been reported yet.

Disclosure of Invention

Aiming at the problems, the invention provides a novel etomidate soft drug compound, which not only has light corticoid inhibition, but also can be a halogenated imidazole compound with short-acting anesthesia effect and quick recovery after continuous administration, so that compared with CPMM or etomidate, the compound can wake up faster and has better waking quality after single injection or continuous infusion, the corticoid function of the body is not inhibited during administration, and the muscle tremor incidence of the animals after anesthesia or anesthesia is low for the administration animals. On the basis, the invention also provides a preparation method of the compound and application of the compound in preparing a central inhibitory drug which has sedative-hypnotic and/or anesthetic effects on human beings or animals.

The halogenated imidazole compound with the short-acting anesthesia function and the quick recovery has the structure shown in the formula (I):

c in formula (I) is R type chiral carbon, R₁And R₂Can be independently selected from H, methyl, ethyl, cyclopropyl, cyclobutyl or isopropyl, or R₁And R₂Form C_2～5A support base of (1); r₃Is substituted or unsubstituted C_1～18Saturated or unsaturated aliphatic hydrocarbons, including straight, branched or cyclic aliphatic hydrocarbon groups; x is H or a halogen atom; y is H or a halogen atom;x and Y cannot be H at the same time.

The compounds represented in the above compounds are:

the halogenated imidazole compounds have basicity, so that the halogenated imidazole compounds can form pharmaceutically acceptable salts with corresponding acid molecules, and are preferably sulfonate, hydrobromide, sulfate, hydrochloride and tartrate of the compound shown in the formula (I). These pharmaceutically acceptable salts may also form solvates, such as hydrates.

A part of the preferred preparation method of the compound of formula (I) is characterized in that the target compound of formula (I) is obtained by substitution reaction of halogenated imidazole compound of formula (II) and halide of formula (III), and the reaction process is as follows:

r in the structure of the reactant₁、R₂、R₃X and Y are as defined in claim 1.

Another preferred process for the preparation of compounds of formula (I) is characterized in that a silver salt of compound (II) is prepared and then reacted with compound (III) to give the target compound, in the following manner:

the process for the preparation of intermediate (II) of the above route can be referred to the process described in WO 2017059827.

The pharmaceutically acceptable salt compound of the formula (I) can be obtained by dissolving the compound of the formula (I) in an alcohol or ester solvent, adding a calculated amount of acid, stirring to form salt, and removing the solvent. Among them, preferred salts of formula (I) include, but are not limited to, tartrate, sulfonate, hydrochloride, hydrobromide and sulfate salts.

The pharmaceutically acceptable salt hydrate of the compound of formula (I) can be obtained by dissolving a salt in an aqueous organic solvent for crystallization.

In-vitro decomposition experiments show that the compound can be quickly decomposed under the action of liver homogenate of rats, and the control drug is slowly decomposed within the experimental time, so that the compound has the characteristic of quick metabolism in the liver, and the compound is prompted to be quickly metabolized in vivo, can generate short-acting general anesthesia action, and is favorable for quick recovery after drug withdrawal.

Animal experiments show that the compound with the structure shown in the formula (I) or the pharmaceutically acceptable salt compound thereof has the characteristics of quick response, quick recovery after single administration or continuous infusion, light cortical function inhibition, low probability of muscle tremor of organisms during administration and after drug withdrawal and the like, and the side effect of etomidate is remarkably reduced. Therefore, the compound of formula (I) and the pharmaceutically acceptable salt thereof can be used for preparing central inhibitory medicaments for producing sedative hypnotic and/or anesthetic effects on animals or human beings through intravenous or intravenous routes.

The foregoing aspects of the present invention will be described in further detail with reference to specific embodiments. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. Various substitutions and alterations according to the general knowledge and conventional practice in the art are intended to be included within the scope of the present invention without departing from the technical spirit of the present invention as described above.

Detailed Description