Imidazole derivative, preparation method and medical application thereof
阅读说明：本技术 一种咪唑类衍生物及其制备方法和在医药上的应用 (Imidazole derivative, preparation method and medical application thereof ) 是由 张晨 赵明亮 谷禾 余彦 李瑶 严庞科 于 2020-09-08 设计创作，主要内容包括：本发明提供一种通式(I)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶及其制备方法和医药上的应用。(The invention provides a compound shown in a general formula (I) or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, and a preparation method and medical application thereof.)
1. a compound of formula (I) or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
R1Each independently selected from H, D, F, Cl, Br, I, OH, NH2Cyano, CF3、CD3、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy or C3-6Cycloalkyl, said alkyl, alkenyl, alkynyl, alkoxyThe radical or cycloalkyl is optionally further substituted by 0 to 4 substituents selected from H, D, F, Cl, Br, I, OH, NH2Cyano, CF3、C1-4Alkyl radical, C1-4Alkoxy or C3-6Cycloalkyl, substituted with a substituent;
R2selected from H, D or F;
R3、R4、R5each independently selected from H or D, provided that R3、R4Or R5At least one of them is selected from D;
R6selected from H, D, F, Cl, Br, I, OH, NH2Cyano, CF3、CD3、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy or C3-6Cycloalkyl, said alkyl, alkenyl, alkynyl, alkoxy or cycloalkyl optionally further substituted by 0 to 4 substituents selected from H, D, F, Cl, Br, I, OH, NH2Cyano, CF3、C1-4Alkyl radical, C1-4Alkoxy or C3-6Cycloalkyl, substituted with a substituent;
R7、R8or R9Each independently selected from H, D or C1-6Alkyl, said alkyl being optionally further substituted by 0 to 4 substituents selected from H, D, F, Cl, Br, I, OH, NH2Cyano, CF3、C1-4Alkyl radical, C1-4Alkoxy or C3-6Cycloalkyl, substituted with a substituent;
n is selected from 0, 1,2 or 3.
2. The compound of claim 1, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof,
R6selected from methyl or CD3；
R7、R8Or R9Is selected from H.
3. The compound of claim 2, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof,
R1each independently selected from H, D, F, Cl, Br, I, OH, NH2Cyano, CF3、CD3、C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl or C1-4Alkoxy, said alkyl, alkenyl, alkynyl or alkoxy is optionally further substituted by 0 to 4 groups selected from H, D, F, Cl, Br, I, OH, NH2Cyano, CF3、C1-4Alkyl or C1-4Substituted by a substituent of alkoxy.
4. The compound of claim 3, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof,
R1each independently selected from H, D, F, Cl, Br, I, OH, NH2Cyano, CF3、CD3Methyl, ethyl, propyl, isopropyl, butyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, methoxy, ethoxy or propoxy, said methyl, ethyl, propyl, isopropyl, butyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, methoxy, ethoxy or propoxy being optionally further substituted by 0 to 4 substituents selected from the group consisting of H, D, F, Cl, Br, I, OH, NH2Cyano, CF3、C1-4Alkyl or C1-4Substituted by a substituent of alkoxy.
5. The compound of claim 4, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof,
R1each independently selected from H, D, F, Cl, Br, I, OH, NH2Cyano, CF3、CD3Methyl, ethyl, propyl, isopropyl, butyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, methoxy, ethoxy or propoxy, said methyl, ethyl, propyl, isopropyl, butyl, vinyl, propenyl, allyl, ethynyl, propylAlkynyl, propargyl, methoxy, ethoxy or propoxy is optionally further substituted with 0 to 4 substituents selected from H, D, F, Cl, Br, I, OH, NH2Cyano, CF3、C1-4Alkyl or C1-4Substituted by a substituent of alkoxy;
R2is selected from H;
R3、R4、R5is selected from D;
R6selected from methyl.
6. The compound of claim 1, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein the compound is selected from the following structures:
7. the compound according to any one of claims 1 to 6, or a stereoisomer, deuterode, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the salt is selected from trifluoroacetate or hydrochloride.
8. A pharmaceutical composition comprising a compound of any one of claims 1-7, or a stereoisomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable carrier.
9. Use of a compound according to any one of claims 1 to 7, or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, in a medicament for sedation or analgesia.
10. Use of a compound according to any one of claims 1-7, or a stereoisomer, deuterode, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, in a medicament for the treatment of delirium, hyperactive delirium, insomnia, attention deficit hyperactivity disorder, benzodiazepines or alcohol or opioid or tobacco withdrawal, premature ejaculation, hypertension, tachycardia, restless leg syndrome, muscle spasticity, hot flashes, anxiety, post-traumatic stress disorder, pain, chronic pelvic pain syndrome, breakthrough cancer pain.
Technical Field
The invention relates to the field of medicines, in particular to imidazole derivatives, a preparation method thereof and application thereof in medicines.
Background
Adrenergic receptors are G-protein coupled receptors, and are classified into adrenergic alpha and beta receptors. Alpha receptors include alpha 1, alpha 2 receptors and beta receptors include beta 1, beta 2, beta 3 receptors. α 2 receptors are widely distributed in the central and peripheral nervous systems and other organ tissues (blood vessels, liver, kidney, pancreas, platelets, etc.). α 2A, α 2B, α 2C are three subtypes of α 2 receptors (Bylund et al, M o l. pharmacol.,1992,42,1-5), and α 2A in the brain is mainly concentrated in the pons and medulla oblongata and is involved in the transmission of sympathetic signals from the center to the periphery. Stimulating presynaptic alpha 2A can regulate the release of adrenalin through a negative feedback mechanism; stimulation of postsynaptic α 2A can cause hyperpolarization of the neuronal cell membrane.
Dexmedetomidine is a highly selective alpha 2 receptor agonist that produces sedation, analgesia, sympathology, diuresis, and chills resistance; can produce sedative hypnotic effect similar to natural sleep, is easy to wake up and has no respiratory depression; dexmedetomidine can be used before, during and after anesthesia; the common adverse reactions are hypotension and bradycardia, and the onset and awakening are relatively slow.
Disclosure of Invention
To achieve better therapeutic efficacy and to better meet market demands, it is desirable to develop a new generation of highly effective α 2 receptor agonists with a faster onset of sedation and/or a shorter time to wake-up. The invention provides an alpha 2 receptor agonist with a novel structure, and finds that the compound with the structure has good activity and shows the advantage of shorter awakening time.
The invention provides a compound shown in a general formula (I) or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, wherein
R1Each independently selected from H, D, F, Cl, Br, I, OH, NH2Cyano, CF3、CD3、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy or C3-6Cycloalkyl, said alkyl, alkenyl, alkynyl, alkoxy or cycloalkyl optionally further substituted by 0 to 4 substituents selected from H, D, F, Cl, Br, I, OH, NH2Cyano, CF3、C1-4Alkyl radical, C1-4Alkoxy or C3-6Cycloalkyl, substituted with a substituent;
R2selected from H, D or F;
R3、R4、R5each independently selected from H or D, provided that R3、R4Or R5At least one of them is selected from D;
R6selected from H, D, F, Cl, Br, I, OH, NH2Cyano, CF3、CD3、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy or C3-6Cycloalkyl, said alkyl, alkenyl, alkynyl, alkoxy or cycloalkyl optionally further substituted by 0 to 4 substituents selected from H, D, F, Cl, Br, I, OH, NH2Cyano, CF3、C1-4Alkyl radical, C1-4Alkoxy or C3-6Cycloalkyl, substituted with a substituent;
R7、R8or R9Each independently selected from H, D or C1-6Alkyl, said alkyl being optionally further substituted by 0 to 4 substituents selected from H, D, F, Cl, Br, I, OH, NH2Cyano, CF3、C1-4Alkyl radical, C1-4Alkoxy or C3-6Cycloalkyl, substituted with a substituent;
n is selected from 0, 1,2 or 3.
Some embodiments of the invention relate to a compound of formula (I) or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
R1Each independently selected from H, D, F, Cl, Br, I, OH, NH2Cyano, CF3、CD3、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy or C3-6Cycloalkyl, preferably H, D, F, Cl, Br, I, OH, NH2Cyano, CF3、CD3、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl or C1-6Alkoxy, more preferably H, D, F, Cl, Br, I, OH, NH2Cyano, CF3、CD3Methyl, ethyl, propyl, isopropylButyl, ethenyl, propenyl, allyl, ethynyl, propynyl, propargyl, methoxy, ethoxy or propoxy, said alkyl, alkenyl, alkynyl, alkoxy or cycloalkyl being optionally further substituted by 0 to 4 substituents selected from H, D, F, Cl, Br, I, OH, NH2Cyano, CF3、C1-4Alkyl radical, C1-4Alkoxy or C3-6Cycloalkyl, substituted with a substituent;
R2selected from H, D or F;
R3、R4、R5each independently selected from H or D, provided that R3、R4Or R5At least one of them is selected from D;
R6selected from H, D, F, Cl, Br, I, OH, NH2Cyano, CF3、CD3、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy or C3-6Cycloalkyl, preferably H, D, F, Cl, Br, I, OH, NH2Cyano, CF3、CD3、 C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl or C1-6Alkoxy, more preferably H, D, F, Cl, Br, I, OH, NH2Cyano, CF3、CD3Methyl, ethyl, propyl, isopropyl, butyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, methoxy, ethoxy or propoxy, said alkyl, alkenyl, alkynyl, alkoxy or cycloalkyl being optionally further substituted by 0 to 4 substituents selected from H, D, F, Cl, Br, I, OH, NH2Cyano, CF3、C1-4Alkyl radical, C1-4Alkoxy or C3-6Cycloalkyl, substituted with a substituent;
R7、R8or R9Each independently selected from H, D or C1-6Alkyl, preferably H, said alkyl being optionally further substituted by 0 to 4 substituents selected from H, D, F, Cl, Br, I, OH, NH2Cyano, CF3、C1-4Alkyl radical, C1-4Alkoxy or C3-6Cycloalkyl, substituted with a substituent;
n is selected from 0, 1,2 or 3.
Some embodiments of the invention relate to a compound of formula (I) or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
R1Each independently selected from H, D, F, Cl, Br, I, OH, NH2Cyano, CF3、CD3、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy or C3-6Cycloalkyl, said alkyl, alkenyl, alkynyl, alkoxy or cycloalkyl optionally further substituted by 0 to 4 substituents selected from H, D, F, Cl, Br, I, OH, NH2Cyano, CF3、C1-4Alkyl radical, C1-4Alkoxy or C3-6Cycloalkyl, substituted with a substituent;
R2selected from H, D or F;
R3、R4、R5each independently selected from H or D, provided that R3、R4Or R5At least one of them is selected from D;
R6selected from methyl or CD3；
R7、R8Or R9Each independently selected from H or D, preferably H;
n is selected from 0, 1,2 or 3.
Some embodiments of the invention relate to a compound of formula (I) or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
R1Each independently selected from H, D, F, Cl, Br, I, OH, NH2Cyano, CF3、CD3、C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl or C1-4Alkoxy, said alkyl, alkenyl, alkynyl or alkoxy is optionally further substituted by 0 to 4 groups selected from H, D, F, Cl, Br, I, OH, NH2Cyano, CF3、C1-4Alkyl or C1-4Substituted by a substituent of alkoxy;
R2selected from H, D or F;
R3、R4、R5each independently selected from H or D, provided that R3、R4Or R5At least one of them is selected from D;
R6selected from methyl or CD3；
R7、R8Or R9Each independently selected from H or D, preferably H;
n is selected from 0, 1,2 or 3.
Some embodiments of the invention relate to a compound of formula (I) or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
R1Each independently selected from H, D, F, Cl, Br, I, OH, NH2Cyano, CF3、CD3Methyl, ethyl, propyl, isopropyl, butyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, methoxy, ethoxy or propoxy, said methyl, ethyl, propyl, isopropyl, butyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, methoxy, ethoxy or propoxy being optionally further substituted by 0 to 4 substituents selected from the group consisting of H, D, F, Cl, Br, I, OH, NH2Cyano, CF3、C1-4Alkyl or C1-4Substituted by a substituent of alkoxy;
R2selected from H, D or F;
R3、R4、R5each independently selected from H or D, provided that R3、R4Or R5At least one of them is selected from D;
R6selected from methyl or CD3；
R7、R8Or R9Each independently selected from H or D, preferably H;
n is selected from 0, 1,2 or 3.
Some embodiments of the invention relate to a compound of formula (I) or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
R1Each independently selected from H, D, F, Cl, Br, I, OH, NH2Cyano, CF3、CD3Methyl, ethyl, propyl, isopropyl, butyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, methoxy, ethoxy or propoxy, said methyl, ethyl, propyl, isopropyl, butyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, methoxy, ethoxy or propoxy being optionally further substituted by 0 to 4 substituents selected from the group consisting of H, D, F, Cl, Br, I, OH, NH2Cyano, CF3、C1-4Alkyl or C1-4Substituted by a substituent of alkoxy;
R2selected from H, D or F;
R3、R4、R5is selected from D;
R6selected from methyl or CD3；
R7、R8Or R9Each independently selected from H or D, preferably H;
n is selected from 0, 1,2 or 3.
Some embodiments of the present invention relate to a compound of formula (I) or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein the compound is selected from the following structures:
some embodiments of the present invention relate to a compound of formula (I) or a stereoisomer, a deutero-compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt, or a co-crystal thereof, wherein the salt is selected from a trifluoroacetate salt or a hydrochloride salt.
The invention provides a pharmaceutical composition, which comprises the compound of the general formula (I) or a stereoisomer, a deutero-compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, and a pharmaceutically acceptable carrier.
The compound of the general formula (I) or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof can be applied to medicines with a sedative effect or an analgesic effect.
Use of a compound of formula (I) according to any one of the invention or a stereoisomer, deuterode, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, in a medicament for the treatment of delirium, hyperactive delirium, insomnia, attention deficit hyperactivity disorder, benzodiazepines or alcohol or opioid or tobacco withdrawal, premature ejaculation, hypertension, tachycardia, restless leg syndrome, muscle spasticity, hot flashes, anxiety, post traumatic stress disorder, pain, chronic pelvic pain syndrome, breakthrough cancer pain.
Synthesis method
To accomplish the objects of the present invention, the compounds of the present invention can be prepared by the following scheme:
the first scheme is as follows:
x is selected from Cl, Br, I, OTs (p-toluenesulfonyl) or benzenesulfonate group;
PG1 is selected from amine protecting groups, preferablyPG2 is selected from a silicon-based protecting group, preferably tert-butyldimethylsilyl (TBS);
n、R1、R2、R3、R4、R5and R6The definition of the substituent group in the compound shown in the general formula (I) is the same;
converting the compound of the general formula (M-1) into a compound of the general formula (M-2) through a conventional acyl chloride forming reaction; carrying out nucleophilic substitution reaction on the general formula (L-1) and the general formula (M-2) compound to obtain a general formula (M-3) compound; carrying out nucleophilic addition reaction on the compound of the general formula (M-3) to obtain a compound of a general formula (M-4); carrying out nucleophilic substitution on the compound of the general formula (M-4) and the compound of the general formula (L-2) to obtain a compound of the general formula (M-5); the compound of the general formula (M-5) is subjected to deprotection reaction to obtain a compound of a general formula (M-6); the compound of the general formula (M-6) is hydrogenated to obtain the compound of the general formula (I).
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
Carbon, hydrogen, oxygen, sulfur, nitrogen or halogen referred to in the groups and compounds of the invention all include isotopes thereof, and carbon, hydrogen, oxygen, sulfur, nitrogen or halogen referred to in the groups and compounds of the invention are optionally further replaced by one or more of their corresponding isotopes, wherein isotopes of carbon include isotopes of carbon12C、13C and14c, isotopes of hydrogen including protium (H), deuterium (D, also known as deuterium), tritium (T, also known as deuterium), and isotopes of oxygen including16O、17O and18isotopes of O, sulfur including32S、33S、34S and36isotopes of S, nitrogen include14N and15isotopes of N, F19Isotopes of F, chlorine including35Cl and37cl, isotopes of bromine including79Br and81Br。
"alkyl" means a straight or branched chain saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and further preferably an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neo-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched isomers thereof; the alkyl group may optionally be further substituted by 0 to 6 groups selected from H, D, F, Cl, Br, I, OH, NH2Cyano, CF3、CD3Alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, and alkyl groups as used herein are defined in accordance with the present definition.
"alkenyl" means straight and branched chainMonovalent unsaturated hydrocarbon groups having at least 1, and typically 1,2, or 3 carbon-carbon double bonds, the backbone comprising 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms in the backbone, examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-pentenyl, 2, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1, 3-butadiene, 1, 3-pentadiene, 1, 4-hexadiene, and the like; the alkyl group may optionally be further substituted by 0 to 5 groups selected from H, D, F, Cl, Br, I, OH, NH2Cyano, CF3、CD3Alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, and substituents. Alkenyl groups are present herein, the definition of which is consistent with the present definition.
"alkynyl" refers to straight and branched chain monovalent unsaturated hydrocarbon radicals having at least 1, and typically 1,2 or 3 carbon-carbon triple bonds, and the backbone includes 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms in the backbone, with examples of alkynyl including, but not limited to, ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, and 4-decynyl, and the like; the alkynyl group can be optionally further substituted by 0 to 5 groups selected from H, D, F, Cl, Br, I, OH, NH2Cyano, CF3、CD3Alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, and the like. Alkynyl groups are presented herein, and their definitions are consistent with this definition.
"alkoxy" means-O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butylOxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy and cyclobutoxy. The alkoxy can be optionally further substituted by 0 to 5 groups selected from H, D, F, Cl, Br, I, OH, NH2Cyano, CF3、CD3Alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl. Alkoxy groups, as used herein, are defined in accordance with the present definition.
"cycloalkyl" means a saturated cyclic alkyl group including from 3 to 10 carbon atoms, preferably from 3 to 8 carbon atoms, and more preferably from 3 to 6 carbon atoms in the ring, and examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like; the cycloalkyl can be further selected from H, D, F, Cl, Br, I, OH and NH by 0 to 52Cyano, CF3、CD3Alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl. Cycloalkyl groups, as found herein, are defined consistent with this definition.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. Such as: "alkyl optionally substituted with F" means that the alkyl group may, but need not, be substituted with F, and the description includes the case where the alkyl group is substituted with F and the case where the alkyl group is not substituted with F.
"pharmaceutically acceptable salts" or "pharmaceutically acceptable salts thereof" refer to those salts which retain the biological effectiveness and properties of the free acid or free base, and which are obtained by reaction of the free acid with a non-toxic inorganic or organic base, or of the free acid by reaction with a non-toxic inorganic or organic acid.
"carrier" refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
"excipient" refers to an inert substance added to a pharmaceutical composition to further depend on the administration of the compound.
An "effective dose" refers to an amount of a compound that elicits a physiological or medical response in a tissue, system, or subject that is sought, including an amount of the compound that, when administered to a subject, is sufficient to prevent the onset of, or alleviate to some extent, one or more symptoms of the condition or disorder being treated.
"IC 50" refers to the half inhibitory concentration, which is the concentration at which half of the maximal inhibitory effect is achieved.
Drawings
FIG. 1 shows sedation scores at various time points following administration of Compound 1 to ICR mice
FIG. 2 is the sedation score at each time point following administration of Compound 2c to ICR mice
Detailed Description
The following detailed description is provided for the purpose of illustrating the embodiments and the advantageous effects thereof, and is not intended to limit the scope of the present disclosure.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (and) Mass Spectrometry (MS). NMR shifts (. delta.) are given in units of 10-6 (ppm). NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic spectrometers using deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) and an internal standard of Tetramethylsilane (TMS).
MS was measured by Agilent 6120B (ESI) and Agilent 6120B (APCI).
HPLC was carried out using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18100X 4.6 mm).
Known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from companies such as Tatan technology, Annaiji chemistry, Shanghai Demer, Chengdong chemical, Shaoshan far chemical technology, and Bailingwei technology.
TBS is tert-butyldimethylsilyl.
Example 1: trifluoroacetate salt of 4- [1- [ 3-methyl-2- (trideuteromethyl) phenyl ] ethyl ] -1H-imidazole (Compound 1)
4-[1-[3-methyl-2-(trideuteriomethyl)phenyl]ethyl]-1H-imidazole,trifluoroacetate
The first step is as follows: 2-bromo-3-methyl-benzoyl chloride (1b)
2-bromo-3-methyl-benzoyl chloride
2-bromo-3-methyl-benzoic acid (1a) (5.00g, 23.25mmol) was dissolved in dry dichloromethane (60mL) at room temperature, oxalyl chloride (8.60g, 68.00mmol) was added thereto under nitrogen, and the mixture was reacted at room temperature for 3 h. The reaction solution was concentrated under reduced pressure to give a crude product, 2-bromo-3-methyl-benzoyl chloride (1b) (8.00g), which was used in the next step without purification.
The second step is that: 4- (2-bromo-3-methyl-benzoyl) -2- [ tert-butyl (dimethyl) silyl ] -N, N-dimethylimidazole-1-sulfonamide (1c)
4-(2-bromo-3-methyl-benzoyl)-2-[tert-butyl(dimethyl)silyl]-N,N-dimethyl-imidazole-1-sulfona mide
Under the protection of nitrogen, N-dimethyl imidazole-1-sulfonamide (1 b') (5.30g, 30.00mmol) was dissolved in dry tetrahydrofuran (60mL) and cooled to-78 ℃. N-butyllithium (13mL, 2.50mol/L in hexane) was added dropwise to the reaction solution, and after reacting at that temperature for 30min, a solution of t-butyldimethylchlorosilane (5.00g, 33.17mmol) in tetrahydrofuran (5mL) was added thereto. Slowly heating to room temperature for reaction for 2h, and cooling to-78 ℃. N-butyllithium (13mL, 2.50mol/L in hexane) was again added dropwise to the reaction solution, and after 30min of reaction, a solution of 2-bromo-3-methyl-benzoyl chloride (1b) (8.00g) in tetrahydrofuran (10mL) was added dropwise thereto. Slowly heating to room temperature and reacting for 16 h. Adding saturated ammonium chloride aqueous solution (40mL), and extracting with ethyl acetate (50 mL. times.2); the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 15:1) to give 4- (2-bromo-3 methyl-benzoyl) -2- [ tert-butyl (dimethyl) silyl ] -N, N-dimethylimidazole-1-sulfonamide (1c) (5.00g, 48%) as a white solid.
LCMS m/z＝486，488[M+1]+.
The third step: 4- [1- (2-bromo-3-methyl-phenyl) -1-hydroxy-ethyl ] -2- [ tert-butyl (dimethyl) silyl ] -N, N-dimethylimidazole-1-sulfonamide (1d)
4-[1-(2-bromo-3-methyl-phenyl)-1-hydroxy-ethyl]-2-[tert-butyl(dimethyl)silyl]-N,N-dimethyl-i midazole-1-sulfonamide
4- (2-bromo-3 methyl-benzoyl) -2- [ tert-butyl (dimethyl) silyl ] -N, N-dimethylimidazole-1-sulfonamide (1c) (3.67g,7.54mmol) and dry tetrahydrofuran (20mL) were added to a reaction flask under nitrogen, cooled to 0 deg.C, methylmagnesium bromide (20mL,1.00mol/L in THF) was added dropwise to the reaction flask, warmed to room temperature, and reacted at that temperature for 2 h. Adding saturated ammonium chloride aqueous solution (20mL), and extracting with ethyl acetate (20 mL. times.2); the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 15:1) to give 4- [1- (2-bromo-3-methyl-phenyl) -1-hydroxy-ethyl ] -2- [ tert-butyl (dimethyl) silyl ] -N, N-dimethylimidazole-1-sulfonamide (1d) (3.32g, 88%) as a white solid.
LCMS m/z(ESI)＝502，504[M+1]+。
The fourth step: 2- [ tert-butyl (dimethyl) silyl ] -4- [ 1-hydroxy-1- [ 3-methyl-2- (trideuteromethyl) phenyl ] ethyl ] -N, N-dimethylimidazole-1-sulfonamide (1e)
2-[tert-butyl(dimethyl)silyl]-4-[1-hydroxy-1-[3-methyl-2-(trideuteriomethyl)phenyl]ethyl]-N,N- dimethyl-imidazole-1-sulfonamide
Under the protection of nitrogen, 4- [1- (2-bromo-3-methyl-phenyl) -1-hydroxy-ethyl ] -2- [ tert-butyl (dimethyl) silyl ] -N, N-dimethyl imidazole-1-sulfonamide (1d) (1.00g, 1.99mmol) and dry tetrahydrofuran (20mL) are added into a reaction flask, the temperature is reduced to-78 ℃, N-butyl lithium (2mL, 2.50mol/L in hexane) is dropwise added into the reaction flask, after the reaction is carried out for 30min at the temperature, a tetrahydrofuran (1mL) solution of deuterated iodomethane (0.58g, 4.00mmol) is dropwise added into the reaction flask, after complete dropwise addition, the temperature is slowly raised to room temperature, and the reaction is carried out for 16 h. Adding saturated ammonium chloride aqueous solution (10mL), and extracting with ethyl acetate 20mL × 2; the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 15:1) to give 2- [ tert-butyl (dimethyl) silyl ] -4- [ 1-hydroxy-1- [ 3-methyl-2- (trideuteromethyl) phenyl ] ethyl ] -N, N-dimethylimidazole-1-sulfonamide (1e) (0.80g, 90%) as a white solid.
LCMS m/z＝441[M+1]+
The fifth step: 4- [1- [ 3-methyl-2- (trideuteromethyl) phenyl ] ethenyl ] -1H-imidazole (1f)
4-[1-[3-methyl-2-(trideuteriomethyl)phenyl]vinyl]-1H-imidazole
After 2- [ tert-butyl (dimethyl) silyl ] -4- [ 1-hydroxy-1- [ 3-methyl-2- (trideuteromethyl) phenyl ] ethyl ] -N, N-dimethylimidazole-1-sulfonamide (1e) (0.80g, 1.82mmol) was dissolved in ethanol (10mL) at room temperature, a solution of sodium hydroxide (1.20 g, 30.00mmol) in water (10mL) was added thereto. The temperature is increased to 90 ℃ and the reaction is carried out for 24 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 30:1) to give 4- [1- [ 3-methyl-2- (trideuteromethyl) phenyl ] vinyl ] -1H-imidazole (1f) (0.24g, 70%) as a white solid.
LCMS m/z＝202[M+1]+.
And a sixth step: trifluoroacetate salt of 4- [1- [ 3-methyl-2- (trideuteromethyl) phenyl ] ethyl ] -1H-imidazole (Compound 1)
4-[1-[3-methyl-2-(trideuteriomethyl)phenyl]ethyl]-1H-imidazole,trifluoroacetate
4- [1- [ 3-methyl-2- (trideuteriomethyl) phenyl ] vinyl ] -1H-imidazole (1f) (25mg, 0.12mmol) was dissolved in methanol (1mL) at room temperature, 10% palladium on carbon (15mg) was added to the reaction solution, and the reaction was carried out for 5 hours at that temperature by replacing with hydrogen gas 3 times. The reaction mixture was filtered through celite, the filtrate was concentrated to dryness under reduced pressure, and the crude product was purified by Pre-HPLC (instrument and preparative column: liquid phase was prepared using WATERS 2767, preparative column model Xselect C18, 5 μm, internal diameter x length 19mm x 150 mm). The preparation method comprises the following steps: the crude product was dissolved in dimethyl sulfoxide and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (with 0.1% TFA). Gradient elution method: acetonitrile was eluted with a 5% gradient of 50% (elution time 15min) to give after lyophilization the trifluoroacetate salt of 4- [1- [ 3-methyl-2- (trideuteromethyl) phenyl ] ethyl ] -1H-imidazole (Compound 1) (15mg, 38%).
LCMS m/z＝204[M+1]+.
1H NMR(400MHz,CD3OD)δ8.76(d,1H),7.34(t,1H),7.08-7.03(m,2H),6.82(dd,1H), 4.56(q,1H),2.31(s,3H),1.61(d,3H).
Example 2: 4- [1- [ 3-methyl-2- (trideuteromethyl) phenyl ] ethyl ] -1H-imidazole (Compound 2)
4-[1-[3-methyl-2-(trideuteriomethyl)phenyl]ethyl]-1H-imidazole
4- [1- [ 3-methyl-2- (trideuteriomethyl) phenyl ] vinyl ] -1H-imidazole (1f) (400mg, 1.99mmol) was dissolved in methanol (40mL), and then 10% palladium on carbon (300mg) was added to the reaction solution, which was substituted with hydrogen 3 times, and reacted at that temperature for 5 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated to dryness under reduced pressure to give free 4- [1- [ 3-methyl-2- (trideuteromethyl) phenyl ] ethyl ] -1H-imidazole (compound 2) (300mg, 74%).
LCMS m/z＝204[M+1]+.
1H NMR(400MHz,CD3OD)δ7.55(d,1H),6.99-6.97(m,2H)，6.93-6.88(m,1H)，6.67(t,1H), 4.37(q,1H),2.28(s,3H),1.53(d,3H).
Example 3: hydrochloride salt of 4- [1- [ 3-methyl-2- (trideuteromethyl) phenyl ] ethyl ] -1H-imidazole-P1 (Compound 2b)
Hydrochloride salt of 4- [1- [ 3-methyl-2- (trideuteromethyl) phenyl ] ethyl ] -1H-imidazole-P2 (Compound 2c)
The first step is as follows: 4- [1- [ 3-methyl-2- (trideuteromethyl) phenyl ] ethyl ] -1H-imidazole-P1 (2P1)
4- [1- [ 3-methyl-2- (trideuteromethyl) phenyl ] ethyl ] -1H-imidazole-P2 (2P2)
4- [1- [ 3-methyl-2- (trideuteromethyl) phenyl ] ethyl ] -1H-imidazole (Compound 2) (250mg, 1.23mmol) was submitted to SFC chiral resolution. (apparatus and preparative column: MGII preparative SFC (SFC-14) apparatus; type of column was Whelk O1(S, S), 250X 30mm I.D.,5 μm). The preparation method comprises the following steps: the compound was dissolved in a mixed solution of 12 mL of methanol and 3mL of methylene chloride to prepare a sample solution. Mobile phase system: supercritical carbon dioxide and isopropanol (0.1% ammonia); gradient elution method: 35% isopropanol (0.1% ammonia); eluent flow rate: 70 mL/min; column pressure 100 lbs; the temperature of the chromatographic column is 38 ℃; detection wavelength: 220 nm; retention time: 2P1 retention time 4.99 min; 2P2 retention time 7.15 min). Finally, the mixture was concentrated under reduced pressure at 40 ℃ or lower to give 4- [1- [ 3-methyl-2- (trideuteromethyl) phenyl ] ethyl ] -1H-imidazole-P1 (2P1) (80mg, 32%), 4- [1- [ 3-methyl-2- (trideuteromethyl) phenyl ] ethyl ] -1H-imidazole-P2 (2P2) (100mg, 40%).
The second step is that: hydrochloride salt of 4- [1- [ 3-methyl-2- (trideuteromethyl) phenyl ] ethyl ] -1H-imidazole-P1 (Compound 2b)
4- [1- [ 3-methyl-2- (trideuteromethyl) phenyl ] ethyl ] -1H-imidazole-P1 (2P1) (80mg, 0.39mmol) was added to a bottle shaped as a eggplant containing water (20mL) at room temperature. Under the condition of stirring, the pH value is adjusted to 3-4 by using 1M dilute hydrochloric acid, and the system becomes clear. Lyophilization then yielded hydrochloride salt of 4- [ (1S or R) -1- [ 3-methyl-2- (trideuteromethyl) phenyl ] ethyl ] -1H-imidazole-P1 (compound 2b) (90mg, 95%).
LCMS m/z＝204[M+1]+.
1H NMR(400MHz,DMSO-d6)δ14.32(s,2H),8.99(d,1H),7.47(t,1H),7.08–7.00(m,2H), 6.82(dd,1H),4.50(q,1H),2.26(s,3H),1.52(d,3H).
The third step: hydrochloride salt of 4- [1- [ 3-methyl-2- (trideuteromethyl) phenyl ] ethyl ] -1H-imidazole-P2 (Compound 2c)
4- [1- [ 3-methyl-2- (trideuteromethyl) phenyl ] ethyl ] -1H-imidazole-P2 (2P2) (100mg, 0.49mmol) was added to a bottle shaped as a eggplant containing water (25mL) at room temperature. Under the condition of stirring, the pH value is adjusted to 3-4 by using 1M dilute hydrochloric acid, and the system becomes clear. Lyophilization then yielded hydrochloride salt of 4- [1- [ 3-methyl-2- (trideuteromethyl) phenyl ] ethyl ] -1H-imidazole-P2 (compound 2c) (105mg, 89%).
LCMS m/z＝204[M+1]+.
1H NMR(400MHz,DMSO-d6)δ14.35(s,2H),8.99(d,1H),7.47(t,1H),7.09–7.00(m,2H), 6.83(dd,1H),4.50(q,1H),2.26(s,3H),1.52(d,3H).
The absolute configurations of the compound 2b and the compound 2c are not determined, and the structures of the compound 2b-a and the compound 2b-b are one of the compounds 2b-a and 2b-b in the formula and are enantiomers, namely, when the structure of the compound 2b is the structure of the compound 2b-a, the absolute structure of the compound 2c is the structure of the compound 2b-b in the formula; when the structure of the compound 2b is the structure of the compound 2b-b, the structure of the compound 2c is the structure of the compound 2 b-a.
Biological test example
1. Sedation efficacy evaluation test
ICR mice, male and female half, 6-8 weeks old, 18-20g, total 12. After the animals reach the breeding room, the adaptation period is not less than 3 days. The day before the experiment, fasting was performed and the drinking water was changed to a 20% glucose solution.
On the day of the experiment, animals were weighed and randomly divided into 3 groups of 4 animals each, male and female halves. The saline group, the medetomidine hydrochloride (calculated as free base 0.1 mg/kg) group and the Compound 1 (calculated as free base 0.3 mg/kg) group were used. The injection is administered by tail vein injection, and the administration volume is 10 ml/kg. After dosing was complete, animals were transferred to open field at set time points and sedation behavioural scoring was performed[1]-[3]The scoring items and sequences are shown in table 1. Animals were transferred to cages at the end of scoring.
TABLE 1 animal sedation behavior score sheet
The behavioral scores for each animal were summed, statistically averaged and standard deviation (Mean ± SD), with the statistical level set at 0.05. Statistical analysis was performed using Graphpad Prism software, Kruskal-Wallis nonparametric test. P <0.05 was considered to be statistically different. The scoring results are shown in table 2 and figure 1.
TABLE 2 sedation scores (Mean SD) at various time points after ICR mice dosing
****P＜0.0001
FIG. 1 is a chart of sedation scores at various time points after ICR mouse administration
The sedation behavioral scores of vehicle control mice were consistent with literature reports. After administration for 5min, 1h and 2h, compared with a vehicle control group mouse, the medetomidine hydrochloride is 0.1mpk, and the sedation behavioral score of the compound 10.3 mpk is obviously reduced; at 5h post-dose, the recovery of the sedation score was the same for the compound 10.3 mpk group mice as for the vehicle group, while the sedation score for the medetomidine hydrochloride 0.1mpk group mice was still significantly lower than for the vehicle group.
And (4) conclusion: compound 1 significantly reduced the sedation behavior score in mice, and recovered more rapidly than medetomidine hydrochloride, which reached comparable levels of sedation.
2. Compound 2c sedation efficacy evaluation test
ICR mice, each half of male and female, 6-8 weeks old, 18-20g, 16 in total. After the animals reach the breeding room, the adaptation period is not less than 3 days. The day before the experiment, fasting was performed and the drinking water was changed to a 20% glucose solution.
On the day of the experiment, animals were weighed and randomly divided into 4 groups of 4 animals each with a male and female half. The saline group, dexmedetomidine hydrochloride (calculated as 0.3mg/kg by weight) group and compound 2c (calculated as equimolar to dexmedetomidine hydrochloride 0.1mg/kg, 0.03mg/kg by weight) group were prepared. The injection is administered by tail vein injection, and the administration volume is 10 ml/kg. After dosing was complete, animals were transferred to open field at set time points and sedation behavioural scoring was performed[1]-[3]The scoring items and sequences are shown in table 1. Animals were transferred to cages at the end of scoring.
The behavioral scores for each animal were summed, statistically averaged and standard deviation (Mean ± SD), with the statistical level set at 0.05. Statistical analysis was performed using Graphpad Prism software, Kruskal-Wallis nonparametric test. P <0.05 was considered to be statistically different.
The sedation behavioral scores of vehicle control mice were consistent with literature reports.
The scoring results are shown in table 4 and figure 2.
TABLE 4 sedation score (Mean + -SD) at each time point after ICR mice were administered Compound 2c
P < 0.0001, P <0.05, VS saline
Compared with the vehicle control group mice, the compound 2c 0.03mpk has obviously reduced sedation behavioral score 5min after administration, and 1h partial recovery, 2h recovery is the same as the vehicle group. The compound 2c is 0.1mpk, the dexmedetomidine hydrochloride is 0.03mpk, and the sedation behavioral score is obviously reduced 5min and 1h after administration; at 2h post-dose, there was some recovery in the sedation score of compound 2c 0.1mpk group mice; at 5h post-dose, the recovery of sedation scores was the same for compound 2c 0.1mpk mice as for the vehicle group, and the sedation scores were still significantly lower for dexmedetomidine hydrochloride 0.03mpk mice than for the vehicle group.
And (4) conclusion: compound 2c significantly reduced the sedation behavior score in mice, and recovered more rapidly than dexmedetomidine hydrochloride to a comparable degree of sedation.
3. Compounds 2b and 2c in vitro on adrenergic alpha2ABinding assays for receptors
In the human recombinant CHO-K1 cell, by reaction with a radioligand (, [ 2 ]3H]Rauwolscine) to test compound 2b and compound 2c, respectively, for adrenergic alpha2AThe binding capacity of the receptor. Test concentrations of Compound 2b and Compound 2c were 1X 10-12M,1×10-11M,1×10-10M,1×10-9M,1×10-8M,1×10-7M, detection of free radioligand by competitive binding, calculation of binding inhibition by MathIQTM(ID Business Solutions Ltd., UK) calculation IC50Calculation of Ki by Cheng and Prusoff equationValue of[4]-[6]. The results are shown in Table 4.
TABLE 4 Compound 2c vs. adrenergic alpha2ABinding capacity of receptor
And (4) conclusion: compound 2b and compound 2c para-adrenergic alpha2AThe receptor has a binding effect.
4. Mouse pharmacokinetic testing
Purpose of the experiment: in this test, a single dose of a test substance is intravenously administered to ICR mice, and the plasma test substance concentration of the mice is measured to evaluate the pharmacokinetic profile of the test substance in the mice.
Test animals: male ICR mice, about 20g, 10-12 weeks old, 12/compound. Purchased from Woods laboratories Inc.
The test method comprises the following steps: on the day of the experiment, 12 ICR mice were randomly grouped by body weight. The food is fasted for 12-14 h before administration for 1 day, and is fed for 4h after administration.
*Dosages are in free base;
sampling
Before and after administration, isoflurane anesthesia is performed, 0.06ml blood is taken out through eye socket, and the obtained product is placed in EDTAK2Centrifuging the tube. Centrifuging at 5000rpm and 4 deg.C for 10min, and collecting plasma.
Plasma collection time points: 0,5min,15min,30min,1,2,3,4,6 and 8 h;
all samples were stored at-80 ℃ before analytical testing. The samples were tested by LC-MS/MS. The results are shown in Table 5.
TABLE 5 dexmedetomidine hydrochloride, Compound 2c mouse PK data
And (4) conclusion: compound 2c has a shorter half-life, higher clearance and more rapid sedation recovery than dexmedetomidine hydrochloride.
Reference to the literature
[1] Liu Yan, FOB and establishment and application of an implanted telemetering system [ D ]. Chinese people liberty military medical science institute, 2011;
[2]Psychopharmacologia(Berl.)13,222--257(1968)；
[3]Precedex，NDA.
[4]Gleason MM and Hieble JP(1991)Ability of SK&F 104078and SK&F 104856to identify alpha-2 adrenoceptor subtypes in NCB20 cells and guinea pig lung.J Pharmacol Exp Ther.259(3): 1124-1132.
[5]Lalchandani SG,Lei L,Zheng W,Suni MM,Moore BM,Liggett SB,Miller DD and Feller DR(2002)Yohimbine dimers exhibiting selectivity for the human alpha 2C-adrenoceptor subtype.J Pharmacol Exp Ther.303(3):979-984.
[6]Cheng,Y.,Prusoff,W.H.,Biochem.Pharmacol.22:3099-3108,1973。
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