Yohimbine derivative as well as preparation method, pharmaceutical composition and application thereof

Abstract

The invention discloses a yohimbine derivative as well as a preparation method, a pharmaceutical composition and application thereof, the structure of the yohimbine derivative is as shown in formula I. In the formula, the definition of each substituent group is as described in the specification and claims. The yohimbine derivative disclosed by the invention is used as an alpha2A-AR antagonist and can be used for treating diseases such as diabetes mellitus and diabetic nephropathy.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of biological medicine, in particular to a class of α2A-AR antagonists, specifically to a class of yohimbine derivatives, a preparation method thereof, and a pharmaceutical composition comprising the compound, the use in the preparation of α2A-AR antagonists, and the use in the preparation of drugs for treating diabetes and diabetic nephropathy. BACKGROUND

[0002] Alpha2-adrenergic receptor (α2-AR) belongs to the G protein-coupled receptor (GPCR) superfamily members, and is very important for regulating catecholamine signaling. In pharmacology, a2-AR is divided into three subtypes: α2A-AR, α2B-AR and α2C-AR. Among them, α2A-AR is widely distributed in the central nervous system (CNS) and peripheral tissues, and is mainly in the former, accounting for about 90% of α2-AR in the CNS. α2A-AR can inhibit the excitation of neurons and the release of norepinephrine and other neurotransmitters, and mediate a series of important physiological responses and pharmacological effects. Several polymorphisms of the coding gene ADRA2A of α2A-AR have been identified, which can increase the expression of α2A-AR, reduce the antidepressant response, and change memory and behavior in different ways.

[0003] Studies have shown that a genetic variant of ADRA2A gene is closely related to type 2 diabetes (T2D): the excess α2A-AR produced in the pancreatic beta cells of carriers of risk allele rs553668 can inhibit the docking of insulin granules to the plasma membrane, resulting in a decrease in the arrangement of insulin-containing vesicles on the cell membrane, and further affecting the release level of insulin (Science, 2010, 327, 217-220; N. Engl. J. Med., 2010, 362, 361-362). Subsequent studies have confirmed that yohimbine, an α2A-AR antagonist, can significantly improve the insulin secretion deficiency associated with ADRA2A risk variants in patients (Sci. Transl. Med., 2014, 6, 257ra139). Since the decrease in the secretion capacity of pancreatic beta cells is one of the main characteristics of T2D, blocking α2A-AR signaling may be a new treatment method specifically targeting the pancreatic beta cell defects of 40% of T2D patients carrying the rs553668 risk variant.

[0004] The a2A-AR plays an important role in the kidney. In the kidney, efferent sympathetic nerves can promote tubular cell apoptosis, inflammation and fibrosis through the secretion of norepinephrine via a2-AR (Kidney Res Clin Pract, 2019, 38, 6-14). Renal nerve ablation can inhibit the effect of the sympathetic nerve / norepinephrine / a2-AR pathway, which can significantly improve acute and chronic kidney injury. Further experiments reveal the key role of the a2A-AR signaling pathway in this process (J Am Soc Nephrol, 2013, 24, 229-242; Kidney International, 2015, 87, 350-358). The use of a2A-AR antagonists (yohimbine, etc.) can significantly improve acute kidney injury (Eur J Pharmacol., 2016, 781: 36-44; Eur J Pharmacol., 2020, 871: 172917.) and chronic kidney injury (J Am Soc Nephrol, 2013, 24, 229-242; Kidney International, 2015, 87, 350-358; J Pharmacol Sci., 2021, 145(1): 79-87.). In summary, given the role of a2A-AR in pancreatic beta cells and the kidney, blocking a2A-AR signaling can simultaneously improve glycemic homeostasis and kidney function, and is a new treatment for patients with diabetic nephropathy.

[0005] Yohimbine has been used in the treatment of male erectile dysfunction in the clinic, and its pharmacokinetics has been well characterized. Common side effects include dizziness, anxiety, restlessness, insomnia, hypertension, and palpitations, which are mainly caused by presynaptic a2A-AR blockade in the CNS, sympathetic nerve activation (EFSA.J., 2013, 11, 3302). Although yohimbine has a significant effect on correcting insulin secretion defects, common central side effects make it unsuitable as a candidate drug for the treatment of T2D and diabetic nephropathy, so it needs to be structurally optimized.

[0006] Currently, there are few reports on the structural modification of yohimbine, mainly focusing on the conversion of the 16-position ester group to an amide to investigate the binding affinity of the derivative to a2-AR subtypes (J. Pharmacol. Exp. Ther., 2002, 303, 979-984; Bioorg. Med. Chem. Lett., 2005, 15, 2758-2760; J. Pharmacol. Exp. Ther., 2006, 319, 739-748). To date, there have been no reports on the a2A-AR antagonistic activity and tissue distribution of new yohimbine derivatives. SUMMARY

[0007] The present application aims to provide a yohimbine derivative as an antagonist of α2A adrenergic receptor (α2A-AR).

[0008] In a first aspect, the present application provides a compound represented by Formula (I), a deuterated compound thereof, or a pharmaceutically acceptable salt thereof,

[0009]

[0010] in the formula, R 1 , R 2 , R 3 and R 4 are each independently hydrogen, halogen, cyano, hydroxyl, ethynyl, substituted or unsubstituted C1-C6 alkyl, C3-C10 cycloalkyl, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl, wherein R is C1-C6 alkyl, C3-C10 cycloalkyl, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl, and X is O or NR a ; wherein R a is selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl;

[0011] R 5 and R 6 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, C3-C10 cycloalkyl, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein R b is selected from the group consisting of C1-C6 alkyl, C3-C10 cycloalkyl, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl, and X is O or NR c ; wherein R c is selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl;

[0012] L 1 is absent, hydrogen, substituted or unsubstituted C1-C6 alkylene, C3-C10 cycloalkyl, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl, wherein R is C1-C6 alkyl, C3-C10 cycloalkyl, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl, and X is O or NR a ; wherein R a is selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl;

[0013] R 7 is absent, hydrogen, substituted or unsubstituted C1-C6alkoxy, C3-C10cycloalkyl, C6-C10aryl, 3-7 membered heterocyclyl, 5-7 membered heteroaryl, wherein R is C1-C6alkyl, C3-C10cycloalkyl, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, C6-C10aryl, 5-7 membered heteroaryl, and X is O or NR a ; wherein R a is hydrogen, C1-C6alkyl, C3-C10cycloalkyl;

[0014] L 1 , R 7 substituents can be annelated to form a 3-7 membered alkyl ring, 4-7 membered heteroalkyl ring, 6 membered aryl ring, or 5-7 membered heteroaryl ring;

[0015] The above substituents mean that the hydrogens on the group are replaced with one or more substituents selected from the group consisting of halogen, hydroxyl, cyano, C1-C6haloalkyl (such as trifluoromethyl), alkynyl, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkoxy (such as trifluoromethoxy), NR d R e , wherein R d and R e are each independently hydrogen, C1-C6alkyl.

[0016] In another preferred embodiment, R 1 is hydrogen, halogen, cyano, hydroxyl, ethynyl, C1-C6alkyl;

[0017] R 2 is hydrogen, halogen, cyano, hydroxyl, ethynyl, C1-C4alkyl, wherein R is substituted or unsubstituted C1-C4alkyl, and X is O, NR a ; wherein R a is hydrogen, C1-C4alkyl, wherein the substitution means that the hydrogens on the group are replaced with one or more substituents selected from the group consisting of halogen, hydroxyl, C1-C4alkyl, NR d R e , wherein Rdand R e are each independently hydrogen, C1-C4alkyl;

[0018] R 3 is hydrogen, halogen, cyano, hydroxyl, C1-C4alkyl, Where R is a substituted or unsubstituted group of the following: C1-C4 alkyl, X is O, and wherein the substitution refers to the substitution of a hydrogen atom on the group by one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, C1-C6 alkyl, NR. d R e , where R d and R e Each is independently hydrogen or C1-C4 alkyl;

[0019] R 4 It can be hydrogen, halogen, cyano, or hydroxyl.

[0020] In another preferred embodiment, R 1 It consists of hydrogen and fluorine.

[0021] In another preferred embodiment, R 2 It can be hydrogen, fluorine, chlorine, bromine, cyano, hydroxyl, ethynyl, methyl, or methoxy.

[0022] In another preferred embodiment, R 3 It can be hydrogen, fluorine, hydroxyl, ethynyl, methyl, or methoxy.

[0023] In another preferred embodiment, R 4 It is hydrogen.

[0024] In another preferred embodiment, R 5 Hydrogen, C1-C4 alkyl, Where R b The following groups may be substituted or unsubstituted: C1-C4 alkyl, C3-C6 cycloalkyl, C6-C10 aryl, 5-7 heteroaryl, wherein the substitution refers to the substitution of a hydrogen atom on the group by one or more substituents selected from the group consisting of: halogen, hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, NR d R e , where R d and R e Each is independently hydrogen or C1-C4 alkyl;

[0025] R 6 Hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, Where R b The following groups may be substituted or unsubstituted: C1-C4 alkyl, wherein the substitution refers to the substitution of a hydrogen atom on the group by one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, trifluoromethyl, NR. d R e , where R d and R e Each is independently hydrogen or C1-C4 alkyl.

[0026] In another preferred embodiment, R 5hydrogen, C1-C3 alkyl, acetyl.

[0027] In another preferred embodiment, R 6 hydrogen, C1-C3 alkyl, acetyl.

[0028] In another preferred embodiment, L 1 is absent, hydrogen, substituted or unsubstituted C1-C4 alkylene, C3-C8 cycloalkyl, 5-7 membered heterocycloalkyl with 1-3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl, wherein R is C1-C4 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocycloalkyl with 1-3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl, and X is O or NR a ; wherein R a is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, wherein the substitution means that a hydrogen on the group is replaced by one or more substituents selected from the group consisting of halogen, hydroxyl, cyano, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, NR d R e , wherein R d and R e are each independently hydrogen, C1-C4 alkyl.

[0029] In another preferred embodiment, L 1 is absent, hydrogen, substituted or unsubstituted C1-C4 alkylene, C3-C6 cycloalkyl, 5-7 membered heterocycloalkyl with 1-3 heteroatoms; wherein the substitution means that a hydrogen on the group is replaced by one or more substituents selected from the group consisting of halogen, hydroxyl, cyano, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, NR d R e , wherein R d and R e are each independently hydrogen, C1-C4 alkyl.

[0030] In another preferred embodiment, R 7 is absent, hydrogen, substituted or unsubstituted C1-C4 alkoxy, C3-C6 cycloalkyl, C6-C10 aryl, 5-7 membered heterocyclyl, 5-7 membered heteroaryl, wherein R is C1-C6 alkyl, C3-C10 cycloalkyl, 4-7 membered heterocycloalkyl with 1-3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl, and X is O or NR a ; wherein R a is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl;

[0031] R 7The substituents spaced apart by 0 to 2 atoms can be annelated to a 3- to 7-membered alkyl ring, a 4- to 7-membered heteroalkyl ring, a 6-membered aromatic ring, a 5- to 7-membered heteroaromatic ring,

[0032] wherein the substituents are selected from the group consisting of halogen, hydroxy, cyano, C1-C4haloalkyl (such as trifluoromethyl), C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkoxy (such as trifluoromethoxy), NR d R e , wherein R d and R e are each independently hydrogen, C1-C4alkyl.

[0033] In another preferred embodiment, R 7 is absent, hydrogen, a substituted or unsubstituted C1-C4alkoxy, C3-C6cycloalkyl, phenyl, 5- to 7-membered heterocyclyl, 5- to 7-membered heteroaryl;

[0034] wherein the substituents are selected from the group consisting of halogen, hydroxy, cyano, C1-C4haloalkyl (such as trifluoromethyl), C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkoxy (such as trifluoromethoxy), NR wherein R d and R e are each independently hydrogen, C1-C4alkyl.

[0035] R 7 The substituents spaced apart by 0 to 2 atoms can be annelated to a 6-membered aromatic ring, a 5- to 7-membered heteroaromatic ring.

[0036] In another preferred embodiment, L 1 and R 7 are of formula V:

[0037]

[0038] wherein r1 is selected from 1, 2 or 3; r2 is selected from 0, 1, 2 or 3;

[0039] Ring B is phenyl, 5- to 6-membered heterocyclyl, C3-C6cycloalkyl, 5- to 6-membered heteroaryl;

[0040] each R is independently selected from the group consisting of halogen, hydroxy, cyano, C1-C4haloalkyl, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkoxy, NR d R e , wherein R d and R e are each independently hydrogen, C1-C4alkyl; or

[0041] two R f form, together with the adjacent C on ring B, a phenyl ring, a 5- to 7-membered heteroaromatic ring.

[0042] In another preferred embodiment, ring B is a phenyl ring, and the substituents thereon are located in the para position relative to L 1 .

[0043] In another preferred embodiment, the compound of formula V has the following structure:

[0044]

[0045] wherein r1 is selected from 1, 2, or 3; r2 is selected from 0, 1, 2, or 3;

[0046] Z1, Z2, Z3 are each independently selected from O, S, N, CH;

[0047] each R f is independently selected from the group consisting of: halogen, hydroxy, cyano, C1-C4 haloalkyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, NR d R e , wherein R d and R e are each independently hydrogen, C1-C4 alkyl; or

[0048] two R f form, together with the adjacent C on the ring, a phenyl ring. In another preferred embodiment, r1 is selected from 1 or 2.

[0049] In another preferred embodiment, r2 is selected from 1 or 2.

[0050] In another preferred embodiment, Z1, Z2, Z3 are each independently selected from O, N, CH.

[0051] In another preferred embodiment, each R f is independently selected from the group consisting of: fluorine, chlorine, bromine, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, NR d R e , wherein R d and R e are each independently hydrogen, methyl, ethyl; or

[0052] two R f form, together with the adjacent C on the ring, a phenyl ring.

[0053] In another preferred embodiment, -L 1 -R 7 is selected from:

[0054]

[0055] The number of substituents Rf on the phenyl ring or benzo-heteroaromatic ring is 0, 1, 2 or 3, preferably 0, 1 or 2.

[0056] In another preferred embodiment, -L 1 -R 7 is selected from the group consisting of: -CH3,

[0057] In another preferred embodiment, the compound is selected from C1-C35.

[0058] In a second aspect of the present application, there is provided a process for preparing a compound of the first aspect, comprising: using as starting material a compound of formula (I), wherein the substituents are as defined above, by converting the carboxy group in position 16 into an oxadiazole structure.

[0059] In a preferred embodiment, the compound or pharmaceutically acceptable salt thereof is prepared by the following route:

[0060]

[0061] reacting a compound of formula H1 with a compound of formula H2 under condensing agent conditions to give a compound of formula H3;

[0062] subjecting a compound of formula H3 to intramolecular condensation cyclization under heating conditions to give a compound of formula H4;

[0063] when L 1 is methylene and R 7 is a phenyl group substituted with iodo, the compound of formula H4 is subjected to a coupling reaction under metal palladium catalysis conditions to give a compound of formula H4, wherein L 1 is methylene and R 7 is a phenyl group substituted with cyano;

[0064] when L 1 is methylene and R 7 is a phenyl group substituted with cyano, the compound is subjected to oxidation with hydrogen peroxide under basic conditions to give a compound of formula H4, wherein L 1 is methylene and R 7 is a phenyl group substituted with ;

[0065] when L 1 is methylene and R 7 is a phenyl group substituted with methyl ester, the compound of formula H4 is subjected to a hydrolysis reaction to give a compound of formula H4, wherein L 1 is methylene and R 7 is a phenyl group substituted with carboxy;

[0066] wherein the substituents are as defined above.

[0067] In a third aspect, the present application provides a pharmaceutical composition comprising: a compound of general formula (I) as described in the first aspect, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

[0068] In a fourth aspect, the present application provides use of a compound of general formula (I) as described in the first aspect or a pharmaceutical composition as described in the third aspect, (i) for the preparation of an alpha2A adrenergic receptor (alpha2A-AR) antagonist; or (ii) for the preparation of a medicament for treating diabetes and diabetic nephropathy.

[0069] In a fifth aspect, the present application provides a method for treating diabetes and diabetic nephropathy, comprising administering to a subject in need thereof a compound of the first aspect or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the third aspect.

[0070] The novel oxadiazole-based yohimbine derivatives of the present application can antagonize alpha2A adrenergic receptors at micromolar concentrations, and have kidney and pancreas targeting properties and significantly reduced brain tissue distribution properties relative to yohimbine.

[0071] It should be understood that, within the scope of the present application, the above technical features of the present application and the various technical features specifically described hereinafter (e.g., in the examples) can be combined with each other to form new or preferred technical solutions. Each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equivalent or similar purpose. Due to the limited space, these will not be repeated one by one. BRIEF DESCRIPTION OF DRAWINGS

[0072] Figure 1 Tissue concentrations (ng / g or ng / mL) of different compounds after 2h of oral gavage at 10mg / kg in mice are shown.

[0073] Figure 2 Tissue concentrations (ng / g or ng / mL) of compound C27 after 0.25, 2 and 8h of oral gavage at 10mg / kg in mice are shown.

[0074] Figure 3 Baseline blood glucose levels of type 2 diabetic mice after a single intraperitoneal injection of yohimbine derivatives (10mg / kg) are shown.

[0075] Figure 4 Glucose tolerance results of type 2 diabetic mice after a single intraperitoneal injection of yohimbine derivatives (10mg / kg) are shown.

[0076] Figure 5 Insulin sensitivity results of type 2 diabetic mice after a single intraperitoneal injection of yohimbine derivatives (10mg / kg) are shown.

[0077] Figure 6 The results of glucose tolerance in type 2 diabetic mice after a single oral administration of a yohimbine derivative (10 mg / kg) are shown.

[0078] Figure 7 The results show the insulin sensitivity of type 2 diabetic mice after a single oral administration of a yohimbine derivative (10 mg / kg).

[0079] Figure 8 The baseline blood glucose levels in type 2 diabetic mice chronically injected with yohimbine derivatives (10 mg / kg, once daily) are shown.

[0080] Figure 9 The results show the effect of chronic administration of yohimbine derivative C27 on random blood glucose in diabetic BTBRob / ob mice. Figure 10 The results show the effect of chronic administration of yohimbine derivative C27 on urine output in diabetic BTBR ob / ob mice.

[0081] Figure 11 The results show the effect of chronic administration of yohimbine derivative C27 on urinary microalbumin excretion in diabetic BTBR ob / ob mice.

[0082] Figure 12 The results show the effect of chronic administration of yohimbine derivative C27 on the urinary microalbumin-creatinine ratio in diabetic BTBR ob / ob mice. Detailed Implementation

[0083] Through extensive and in-depth research, the inventors of this application have, for the first time, developed a class of compounds that maintain good α2A adrenergic receptor antagonistic activity while also possessing pancreatic targeting and low brain permeability. Specifically, these are yohimbine derivatives of the oxadiazole class, characterized by the conversion of the 16-position ester group of yohimbine to an oxadiazole group. This maintains good α2A adrenergic receptor antagonistic activity. Compared to yohimbine, these derivatives exhibit kidney and pancreatic targeting characteristics and significantly reduced brain tissue distribution, eliminating the central nervous system side effects of yohimbine such as anxiety and hypertension. They can significantly improve glucose metabolism and kidney function in type 2 diabetic animal models, and hold promise as novel drugs acting on α2A adrenergic receptors for the treatment of diabetes and diabetic nephropathy. Based on this, the present invention was completed.

[0084] the term

[0085] As used herein, the term "alkyl" preferably refers to a straight or branched chain saturated aliphatic group, non-limiting examples of which include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, and the like. The expression "C1-C6" is intended to include groups having 1, 2, 3, 4, 5, or 6 carbon atoms, e.g., "C1-C6 alkyl" refers to an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms.

[0086] "Alkylene" refers to a straight chain or branched chain saturated aliphatic group having the indicated number of carbon atoms and linking at least two other groups, i.e., a divalent hydrocarbon group. The two groups attached to the alkylene group can be attached to the same or different atoms of the alkylene group. For example, a straight chain alkylene group can be a divalent group of the formula -(CH2)n- where n is 1, 2, 3, 4, 5, or 6. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, and hexylene. n - of the formula -(CH2)n- where n is 1, 2, 3, 4, 5, or 6. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, and hexylene.

[0087] As used herein, the term "halogen" preferably refers to fluorine, chlorine, bromine, or iodine.

[0088] As used herein, the term "alkoxy" refers to -O-(alkyl), where alkyl is as defined above. "C1-C6 alkoxy" refers to an oxygen-containing alkyl group containing 1-6 carbons, non-limiting examples of which include methoxy, ethoxy, propoxy, butoxy, and the like.

[0089] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent group comprising 3 to 20 carbon atoms, preferably comprising 3 to 12 carbon atoms, more preferably the cycloalkyl group comprises 3 to 10 carbon atoms. Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spirocyclic, fused, and bridged cycloalkyl groups.

[0090] As used herein, the term "aryl" refers to a 6- to 10-membered all-carbon monocyclic or fused polycyclic (that is, rings which share pairs of adjacent carbon atoms) group, and the group has a conjugated pi-electron system, for example, phenyl and naphthyl. The aryl ring can be fused with a heterocyclyl, heteroaryl, or cycloalkyl ring, non-limiting examples of which include benzimidazole, benzothiazole, benzoxazole, benzisoxazole, benzopyrazole, quinoline, benzoindole, benzodihydrofuran.

[0091] As used herein, the term "heterocyclyl" refers to a heteroalicyclic ring system comprising 1 to 3 heteroatoms, such as 3 to 7 ring atoms. The heteroatoms of the heterocyclyl group include oxygen, sulfur, and nitrogen. The heterocyclyl group is preferably 3- or 6-membered, for example, oxiranyl, morpholinyl, piperazinyl, and the like.

[0092] In the present specification, the heteroaryl group refers to a heteroaromatic system containing 1 to 4 heteroatoms, such as 5 to 14 ring atoms. The heteroatoms of the heteroaryl group include oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5- or 6-membered, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, imidazolyl, tetrazolyl and the like. The heteroaryl group can be fused to an aryl, heterocyclyl or cycloalkyl ring, in which the ring connected to the parent structure is a heteroaryl ring.

[0093] In the present application, unless otherwise specified, represents a bonding site.

[0094] In the present specification, the pharmaceutically acceptable salt is not particularly limited, and preferably includes inorganic acid salts, organic acid salts, alkylsulfonic acid salts and arylsulfonic acid salts; the inorganic salts include hydrochlorides, hydrobromides, nitrates, sulfates, phosphates and the like; the organic salts include formates, acetates, propionates, benzoates, maleates, fumarates, succinates, tartrates, citrates and the like; the alkylsulfonic acid salts include methanesulfonates, ethanesulfonates and the like; and the arylsulfonic acid salts include benzenesulfonates, p-toluenesulfonates and the like.

[0095] Preparation method

[0096] The oxadiazole-based yohimbine derivative of the present application can be prepared by the following route. The definitions of the substituents are the same as described above.

[0097]

[0098] The present application will be further illustrated by the following examples. It should be understood that these examples are intended to illustrate the present application and are not intended to limit the scope of the present application. The experimental methods in the following examples, for which specific conditions are not indicated, are generally conducted under conventional conditions or under conditions recommended by the manufacturers. Unless otherwise specified, the percentages and parts are percentages by weight and parts by weight.

[0099] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. In addition, any method and material similar or equivalent to those described herein can be used in the practice of the present application. The preferred methods and materials described herein are illustrative only and not intended to be limiting.

[0100] In the following preparation examples, NMR was determined by using a Bruker Avance III 400 / 500 MHz NMR instrument, NMR calibration: δH 7.26 ppm (CDCl3), 2.50 ppm (DMSO-d6); mass spectrum was determined by using an Agilent 1200 Quadrupole LC / MS liquid chromatograph-mass spectrometer; reagents were mainly provided by Shanghai Chemical Reagent Company; TLC thin layer chromatography silica gel plates were produced by Yantai Jiangyou Silica Gel Development Co., Ltd., model HSGF254; normal phase column chromatography silica gel used for compound purification was produced by Qingdao Marine Chemical Factory Branch, model zcx-II, 200-300 mesh.

[0101] The Chinese corresponding to the abbreviations in this paper is as follows:

[0102] DMF: N,N-dimethylformamide; COMU. (1-cyano-2-ethoxy-2-oxoethylideneaminooxy) dimethylamino-morpholino-carbenium hexafluorophosphate; Pd(dba)2: bisbenzylideneacetone palladium; dppf: 1,1'-bis(diphenylphosphino) ferrocene;

[0103] Example 1

[0104]

[0105] (1) Phenylacetonitrile (1.17 g, 10 mmol) was dissolved in ethanol (20 mL), and water (8 mL), sodium carbonate (848 mg, 8 mmol), hydroxylamine hydrochloride (695 mg, 10 mmol) were added in turn, and stirred at room temperature for 24 hours, most of the solvent was removed by reduced pressure concentration, the residue was dissolved in ethyl acetate (80 mL), washed with saturated brine (20 mL x 2), the organic phase was dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The product was directly used in the condensation reaction without purification.

[0106] (2) Hydrastine M1 (7.81 g, 20 mmol) was placed in methanol / tetrahydrofuran / water (90 mL / 60 mL / 30 mL) under ice bath, and lithium hydroxide monohydrate (5.04 g, 120 mmol) was added, and stirred for half an hour under ice bath, then moved to room temperature, and monitored by LC-MS until the raw material disappeared, most of the solvent was removed by reduced pressure concentration, the residue was dissolved in water (150 mL), and the pH was adjusted to the system to appear milky turbidity with 5% hydrochloric acid under ice bath, and stood overnight, and filtered, the filter cake was washed with water (100 mL), the filter cake was collected, and dried to obtain white powder M2 (5.9 g, 17.3 mmol), with a molar yield of 86%.

[0107] (3) M2 (340 mg, 1 mmol) was dissolved in DMF (5 mL) at room temperature, triethylamine (304 mg, 3 mmol) was added, and after stirring for 5 minutes, COMU (428 mg, 1 mmol) was slowly added. After stirring at room temperature for 20 minutes, the crude product (300 mg, 2 mmol) from operation (1) was added, and after stirring at room temperature for 24 hours, the reaction solution was concentrated under reduced pressure to remove the solvent. The residue was dissolved in dichloromethane / methanol (100 mL / 10 mL), washed with saturated brine (20 mL x 3), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (dichloromethane / methanol = 30:1) to obtain a brown foamy solid M3.

[0108] (4) The condensation product M3 from operation (3) was dissolved in 1,4-dioxane (5 mL), and toluene (10 mL) was added. After heating to 100°C under a nitrogen atmosphere, the reaction was stopped after 24 hours, the solvent was removed by concentration under reduced pressure, the residue was dissolved in dichloromethane / methanol (100 mL / 10 mL), washed with saturated brine (20 mL x 3), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (dichloromethane / methanol = 30:1) to obtain a light brown foamy solid C1 (46 mg, 0.1 mmol), with a 10% molar yield for operations (3) and (4).

[0109] Other compounds in the following table were synthesized using the same method as in Example 1, with different cyano substrates:

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117] Example 2

[0118]

[0119] (1) 4-Iodo phenylacetonitrile (2.43 g, 10 mmol) was dissolved in ethanol (20 mL) at room temperature, followed by the addition of water (8 mL), sodium carbonate (848 mg, 8 mmol), hydroxylamine hydrochloride (695 mg, 10 mmol). The mixture was stirred at room temperature for 24 hours. Most of the solvent was removed by reduced pressure concentration. The residue was dissolved in ethyl acetate (80 mL), washed with saturated brine (20 mL x 2), and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure. The product was used directly in the next step without further purification.

[0120] (2) M2 (340 mg, 1 mmol) was dissolved in DMF (5 mL) at room temperature, followed by the addition of triethylamine (304 mg, 3 mmol). After stirring for 5 minutes, COMU (428 mg, 1 mmol) was slowly added. The mixture was stirred at room temperature for 20 minutes. The crude product from step (1) (552 mg, 2 mmol) was added. The mixture was stirred at room temperature for 24 hours. The solvent was removed by reduced pressure concentration. The residue was dissolved in dichloromethane / methanol (100 mL / 10 mL), washed with saturated brine (20 mL x 3), and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure. The product was purified by column chromatography (dichloromethane / methanol = 30:1) to give M3 as a brown foam.

[0121] (3) The condensation product from step (2) was dissolved in 1,4-dioxane (5 mL), followed by the addition of toluene (10 mL). The mixture was heated to 100°C under a nitrogen atmosphere. The reaction was stopped after 24 hours. The solvent was removed by reduced pressure concentration. The residue was dissolved in dichloromethane / methanol (100 mL / 10 mL), washed with saturated brine (20 mL x 3), and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure. The product was purified by column chromatography (dichloromethane / methanol = 30:1) to give M4 as a light brown foam (69 mg, 0.12 mmol). The overall yield for steps (2) and (3) was 12%.

[0122] (4) M4 (58 mg, 0.1 mmol) was dissolved in DMF (5 mL), followed by the addition of Pd(dba)2(5.7 mg, 0.01 mmol), dppf (5.5 mg, 0.01 mmol), and Zn(CN)2(11.7 mg, 0.1 mmol). The mixture was heated to 80°C under a nitrogen atmosphere. The reaction was stopped after 6 hours. The solvent was removed by reduced pressure concentration. The residue was dissolved in dichloromethane / methanol (100 mL / 10 mL), washed with saturated brine (20 mL x 3), and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure. The product was purified by column chromatography (dichloromethane / methanol = 30:1) to give C19 as a light brown foam (33 mg, 0.07 mmol). The overall yield was 70%.

[0123] Other compounds in the following table were synthesized using the same procedure as in Example 2 with different cyano substrates:

[0124]

[0125] Example 3

[0126]

[0127] Compound C19 (14 mg, 0.03 mmol) was dissolved in EtOH (0.15 mL), DMSO (0.075 mL) was added under ice-bath, then 4 M NaOH (0.0073 mL) and 30% H2O2 (0.01 mL) were added, the reaction was carried out under ice-bath for 30 minutes, then the temperature was raised to room temperature, the reaction was stopped after 5 hours, 10% Na2S2O3 (0.15 mL) was added under ice-bath to the reaction system, then H2O (2 mL) was added, white solid was precipitated, the reaction system was filtered under reduced pressure, the filter cake was washed with water, and dried to obtain white solid C27 (10 mg, 0.02 mmol) with a molar yield of 67%.

[0128]

[0129] Example 4

[0130]

[0131] Compound C29 (50 mg, 0.1 mmol) was placed in methanol / tetrahydrofuran / water (2.1 mL / 0.3 mL / 0.6 mL) under ice-bath, lithium hydroxide monohydrate (42 mg, 1 mmol) was added, the temperature was raised to room temperature after stirring under ice-bath for half an hour, LC-MS was monitored until the raw material disappeared, most of the solvent was removed by reduced pressure concentration, water (5 mL) was added to the residue, 5% hydrochloric acid was added under ice-bath to adjust the pH to about 6, the mixture was allowed to stand, filtered, the filter cake was washed with water (2 mL), the filter cake was collected and dried to obtain yellow powder C30 (25 mg, 0.05 mmol) with a molar yield of 50%.

[0132]

[0133] Example 5 α2A-AR antagonist test

[0134] 1. Purpose of the experiment

[0135] To investigate the antagonistic activity of yohimbine derivatives on α2A-AR.

[0136] 2. Principle of the experiment

[0137] By establishing the cell line co-transfected with the target receptor and Ga16, the receptor can be activated to cause the activation of Gα16 protein, and then activate phospholipase C (PLC) to produce IP3 and DAG. IP3 can bind to the IP3 receptor on the endoplasmic reticulum and mitochondria in the cell, thereby causing the release of intracellular calcium. Therefore, the change of intracellular calcium can be used as a method for detecting the activation state of the target receptor. Fluo-4 / AM is a calcium fluorescent probe indicator for measuring calcium ions. As a non-polar lipid-soluble compound, it enters the cell and is dissociated by the action of cell lipase to release Fluo-4; since Fluo-4 is a polar molecule that is not easy to pass through the lipid bilayer membrane, it can keep Fluo-4 in the cell for a long time. Finally, the level of Ga protein activation can be reflected by measuring the excited fluorescence intensity. If the screened compound can agonize the target receptor, the calcium flow reaction can be greatly increased; on the contrary, if the screened compound can antagonize the target receptor, the calcium flow reaction can be greatly reduced.

[0138] 3. Experimental sample

[0139] Before the test, the test compound is dissolved in DMSO to prepare a mother liquor, which is diluted to the required concentration with culture solution when used.

[0140] 4. Experimental method

[0141] The cells stably expressing α2A-AR / Ga16 are seeded in a 96-well plate and cultured overnight; the culture solution in the well seeded with cells is aspirated, and fresh dye (40 μL / well) is added, and incubated at 37°C for 40 minutes; the test drug is diluted with calcium buffer and mixed well; the dye is aspirated and discarded, and then washed with fresh calcium buffer, and then replaced with 50 μL of calcium buffer dissolved with the test drug; detected by FlexStation II instrument, and 25 μL of calcium buffer dissolved with known agonist UK14304 is automatically added by the instrument starting from the 15th second, and the fluorescence value at 525 nm is finally read.

[0142] 5. Experimental results (take 35 compounds in Table 1 as an example, but not limited to these compounds)

[0143] Table 1 Test results of α2A-AR antagonistic activity of compounds

[0144]

[0145]

[0146] Note: IC 50 is the evaluation of the antagonistic activity of the sample drug on α2A-AR.

[0147] * represents 0.5 μM ≤ IC 50<2 μM; ** represents 0.3 μM < IC 50 <0.5 μM,

[0148] *** represents 0.1 μM < IC 50 <0.3 μM; **** represents IC 50 <0.1 μM.

[0149] 6. Results and Discussion

[0150] These compounds were able to compete with α2A-AR agonist UK14304 in cells expressing α2A-AR and antagonize the agonistic effect of UK14304 on α2A-AR with IC 50 See Table 1. The results indicate that these compounds are antagonists of α2A-AR.

[0151] Example 6 Mouse tissue distribution test of yohimbine derivatives

[0152] 1. Purpose of the experiment

[0153] To investigate the tissue distribution of yohimbine derivatives in mice.

[0154] 2. Experimental design

[0155] Table 2 Dosing schedule for mouse tissue distribution test

[0156]

[0157] Note: The compounds were administered as hydrochloride salts in deionized water; the test animals were ICR male mice

[0158] The mice were fasted for more than 12 h during the test period and had free access to water.

[0159] Table 3 Dosing schedule for mouse tissue distribution test of compound C27

[0160]

[0161] Note: The vehicle was composed of 5% DMSO + 5% solutol + 90% saline; the test animals were ICR male mice

[0162] The mice were fasted for more than 12 h during the test period and had free access to water.

[0163] 3. Sample collection and determination

[0164] (1) Mouse tissue distribution test: Each group of animals was sacrificed after anesthesia at 2h after administration, and brain, pancreas, heart, liver and kidney tissues were collected by dissection, washed with physiological saline and stored in a refrigerator at -20°C for testing; 0.3 mL of whole blood was collected into an EDTA-K2 anticoagulant test tube, centrifuged at 11000 rpm for 5 min to separate plasma, and stored in a refrigerator at -20°C for testing.

[0165] Another 3 animals were collected for blank plasma and tissues.

[0166] The concentration of the original drug in plasma and tissues was determined.

[0167] (2) Compound C27 mouse tissue distribution test: After gavage administration, the mice were sacrificed by abdominal aortic exsanguination at the corresponding time points (0.25, 2 and 8h), and brain, heart, liver, lung, pancreas, kidney tissues were immediately collected by dissection, and part of the plasma was collected. Ice water bath operation.

[0168] Centrifugation conditions: centrifugation at 11000 rpm for 5 min to separate plasma (about 200 μL).

[0169] After the collection of tissues and plasma, they were stored below -60°C.

[0170] 4. Experimental results and discussion

[0171] Figure 1 The tissue concentrations (ng / g or ng / mL) of different compounds in mice 2h after gavage administration of 10mg / kg are shown. Figure 1 Four compounds are shown as examples, but are not limited to these compounds

[0172] Figure 2 The tissue concentrations (ng / g or ng / mL) of compound C27 in mice 0.25, 2 and 8h after gavage administration of 10mg / kg are shown.

[0173] The relative ratio of tissue distribution concentration to blood concentration was calculated, and compounds C1, C6, C13, C19 and C27 all showed lower brain tissue distribution than yohimbine. The brain tissue distribution of compound C19 was about forty times lower than yohimbine, and compound C19 also had good pancreas distribution; the plasma exposure of compound C27 was comparable to yohimbine, but its brain tissue distribution was about two hundred and seventy times lower than yohimbine, and it had pancreas distribution characteristics comparable to compound C19.

[0174] Example 7 Test experiment of yohimbine derivative on the treatment effect of reducing blood sugar in diabetic mice

[0175] 1. Purpose of the experiment

[0176] To test whether yohimbine derivative C19 can improve the blood sugar metabolism of type 2 diabetes

[0177] 2. Experiment Content

[0178] This experiment used a type 2 diabetic mouse model induced by a high-sugar, high-fat diet to conduct tests on the following aspects:

[0179] 1) Effects of a single intraperitoneal administration on basal blood glucose, glucose tolerance, and insulin sensitivity in diabetic mice.

[0180] 2) Effects of a single oral gavage administration on glucose tolerance and insulin sensitivity in diabetic mice.

[0181] 3) Effect of continuous chronic intraperitoneal administration on basal blood glucose in diabetic mice.

[0182] 3. Experimental Methods

[0183] C57BL\6J mice were fed a high-sugar, high-fat diet for 3 months. After the average weight of the mice stabilized above 50g and the average basal blood glucose level stabilized above 12mmol / L, the test experiment was carried out.

[0184] Blood glucose levels were primarily assessed using a glucometer to measure tail vein blood. For testing the effect on basal blood glucose, the study was conducted on mice under normal dietary conditions. Pre-administration basal blood glucose levels were measured, followed by a single intraperitoneal injection or a single gavage administration of yohimbine derivative C19 (10 mg / kg mouse body weight). Venous blood glucose levels were measured sequentially at 15, 30, 60, 90, and 120 minutes after administration. Glucose tolerance in mice was tested after a 16-hour overnight feeding. Thirty minutes after a single intraperitoneal injection or gavage administration of yohimbine derivative C19 (10 mg / kg mouse body weight), glucose (1.5 g / kg) was injected intraperitoneally, and venous blood glucose levels were measured sequentially at 15, 30, 60, 90, and 120 minutes. Insulin sensitivity in mice was assessed after a 6-hour feeding. Thirty minutes after a single intraperitoneal injection or gavage administration of yohimbine derivative C19 (10 mg / kg mouse body weight), insulin (1 UI / kg) was administered intraperitoneally. Venous blood glucose levels were measured at 15, 30, 60, 90, and 120 minutes. For the effect of chronic administration on blood glucose levels, diabetic mice were intraperitoneally injected with yohimbine derivative C19 (10 mg / kg) daily for 12 consecutive days. Basal blood glucose levels were measured daily before drug injection under free-flowing diet. The control group received either saline injection or gavage.

[0185] 4. Experimental Results

[0186] Experimental results are as follows Figures 3-8 As shown. Among them Figure 3Results showed that a single i.p. injection of yohimbine derivative (10 mg / kg) significantly reduced the basal blood glucose level in diabetic mice. Figure 4 Results showed that a single i.p. injection of yohimbine derivative (10 mg / kg) significantly improved glucose tolerance in diabetic mice. Figure 5 Results showed that a single i.p. injection of yohimbine derivative (10 mg / kg) significantly improved insulin sensitivity in diabetic mice. Figure 6 Results showed that a single gavage of yohimbine derivative (10 mg / kg) significantly improved glucose tolerance in diabetic mice. Figure 7 Results showed that a single gavage of yohimbine derivative (10 mg / kg) significantly improved insulin sensitivity in diabetic mice. Figure 8 Results showed that chronic injection of yohimbine derivative (10 mg / kg, once a day) significantly reduced the basal blood glucose level in diabetic mice.

[0187] 5Results and Discussion

[0188] This experiment showed that a single injection or gavage of yohimbine derivative C19 of the present application could significantly reduce the high blood glucose level in diabetic mice, and could improve glucose tolerance and increase insulin sensitivity. Chronic administration could stabilize the basal blood glucose level of diabetic mice at a level closer to normal. Therefore, yohimbine derivative C19 of the present application had a significant effect on improving blood glucose metabolism in diabetic mice.

[0189] Example 8 Evaluation of the therapeutic effect of yohimbine derivative C27 on diabetic nephropathy

[0190] 1. Purpose of the experiment

[0191] The improvement of diabetic nephropathy in BTBR ob / ob mice by long-term administration of yohimbine derivative C27 was investigated.

[0192] 2. Experimental design

[0193] 38 BTBR ob / ob mice (24 male, 24 female), 5 weeks old, were brought into the animal house of the institute and raised until 7 weeks old when the experiment began. All BTBR ob / ob mice were collected 6h urine 10 days before administration, recorded urine volume, and detected urine microalbumin and creatinine levels. Random blood glucose and random body weight were measured in the morning 2 days before administration, and then fasting blood glucose and fasting body weight were measured after fasting for 6 hours (without water). According to the blood glucose, body weight, urine volume, 6h urine microalbumin excretion and urine microalbumin creatinine ratio content of the mice, the mice were divided into 4 groups, 12 in each group (6 male and 6 female). They were model control group, yohimbine derivative C27 1, 3 and 10 mg / kg dose groups, and a group of BTBR ob / ob mice littermate normal mice as normal control. Oral gavage administration, the administration volume was 10 ml / kg, once a day.

[0194] 3. Index detection

[0195] The blood glucose of the normal control group, model control group, each administration group and positive control group mice was detected every 2 weeks after the first administration; urine was collected every 4 weeks to detect urine volume, urine microalbumin and creatinine levels, and calculate urine microalbumin excretion and microalbumin creatinine ratio.

[0196] 4. Experimental results

[0197] (1). The effect of long-term administration of yohimbine derivative C27 on blood glucose of diabetic BTBR ob / ob mice

[0198] Figure 9 The results of the effect of chronic administration of yohimbine derivative C27 on random blood glucose of diabetic BTBR ob / ob mice, wherein *p<0.05, compared with the model group; **p<0.01, compared with the model control group.

[0199] Figure 9 It is shown that the random blood glucose of the model control group of diabetic BTBR ob / ob mice was significantly higher than that of the normal control group during the test period, and maintained at a relatively stable level. Chronic administration of yohimbine derivative C27 for 6 weeks can significantly reduce the random blood glucose of diabetic BTBR ob / ob mice, and the effect lasts until the end of administration. It is thus shown that yohimbine derivative C27 can dose-dependently reduce the random blood glucose of diabetic BTBR ob / ob mice.

[0200] (2). The effect of long-term administration of yohimbine derivative C27 on urine volume of diabetic BTBR ob / ob mice

[0201] Figure 10The results of the effect of chronic administration of yohimbine derivative C27 on urine volume of diabetic BTBR ob / ob mice, wherein *p<0.05, compared with the model group; **p<0.01, compared with the model control group.

[0202] Figure 10 It is shown that the urine volume of the model control group of diabetic BTBR ob / ob mice was significantly higher than that of the normal control group during the test period. Chronic administration of yohimbine derivative C27 for 4 weeks can dose-dependently reduce the urine volume of diabetic BTBR ob / ob mice, and the effect lasts until administration for 8 weeks. It is thus shown that yohimbine derivative C27 can dose-dependently reduce the urine volume of diabetic nephropathy mice.

[0203] (3). The effect of long-term administration of yohimbine derivative C27 on urinary microalbumin of diabetic BTBR ob / ob mice

[0204] Figure 11 The results of the effect of chronic administration of yohimbine derivative C27 on urinary microalbumin excretion of diabetic BTBR ob / ob mice, wherein *p<0.05, compared with the model group; **p<0.01, compared with the model control group.

[0205] Figure 11 It is shown that the 6h urinary microalbumin excretion of the model control group of diabetic BTBR ob / ob mice was significantly higher than that of the normal control group during the test period. Chronic administration of yohimbine derivative C27 for 4 weeks can dose-dependently reduce the 6h urinary microalbumin excretion of diabetic BTBR ob / ob mice, and the effect lasts until administration for 8 weeks. It is thus shown that chronic administration of yohimbine derivative C27 can significantly improve the 6h urinary microalbumin excretion of diabetic nephropathy mice.

[0206] (4). The effect of long-term administration of yohimbine derivative C27 on urinary microalbumin creatinine ratio of diabetic BTBR ob / ob mice

[0207] Figure 12 The results of the effect of chronic administration of yohimbine derivative C27 on urinary microalbumin creatinine ratio of diabetic BTBR ob / ob mice, wherein *p<0.05, compared with the model group; **p<0.01, compared with the model control group.

[0208] Figure 12 It is shown that the urinary microalbumin creatinine ratio of the model control group of diabetic BTBR ob / ob mice was significantly higher than that of the normal control group during the test period. Chronic administration of yohimbine derivative C27 for 4 weeks can dose-dependently reduce the urinary microalbumin creatinine ratio of diabetic BTBR ob / ob mice, and the effect lasts until administration for 8 weeks. It is thus shown that chronic administration of yohimbine derivative C27 can significantly improve diabetic nephropathy.

[0209] 5Results and Discussion

[0210] The experiment shows that the yohimbine derivative C27 of the application can significantly reduce the blood glucose, urine volume, urinary albumin excretion and urinary albumin creatinine ratio of the diabetic BTBR ob / ob mice by chronic intragastric administration. Therefore, the yohimbine derivative C27 of the application has obvious effect of improving diabetic nephropathy.

[0211] The structural modification of yohimbine obtains a new derivative with improved α2A adrenergic receptor antagonistic activity, pancreatic and kidney targeting and reduced brain tissue distribution. The lower brain tissue distribution eliminates the central side effects of yohimbine such as anxiety and elevated blood pressure. The compound of the application can significantly improve the blood glucose metabolism of the animal model of type 2 diabetes, and chronic administration can stabilize the basal blood glucose level of the diabetic mice, and further improve the urine volume, urinary albumin excretion and urinary albumin creatinine ratio of the diabetic mice, which is expected to be used for the treatment of diabetes and diabetic nephropathy.

[0212] All the documents mentioned in the application are cited as references in the present application, as if each document is cited as a reference individually. In addition, it should be understood that, after reading the above teaching of the application, those skilled in the art can make various modifications or amendments to the application, and these equivalent forms also fall within the scope defined by the claims attached to the present application.

Claims

1. A compound of general formula (I), its deuterated compound, or a pharmaceutically acceptable salt thereof, In the formula, R 1 R 2 R 3 and R 4 Each of the following groups, independently hydrogen, halogen, cyano, hydroxyl, ethynyl, or substituted or unsubstituted: C1-C6 alkyl, C3-C10 cycloalkyl, 4-7 membered heterocyclic alkyl containing 1-3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl, ... Where R is one of the following groups: C1-C6 alkyl, C3-C10 cycloalkyl, 4-7 membered heterocyclic alkyl containing 1-3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl, and X is O or NR. a ;where R a Selected from: hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl; R 5 and R 6 Each of the following groups, independently hydrogen, substituted or unsubstituted: C1-C6 alkyl, C3-C10 cycloalkyl, 4-7 membered heterocyclic alkyl containing 1-3 heteroatoms, Where R b Selected from: C1-C6 alkyl, C3-C10 cycloalkyl, 4-7 membered heterocyclic alkyl containing 1-3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl, where X is O or NR. c ;where R c Selected from: hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl; L 1 The following groups are absent, hydrogen-containing, substituted, or unsubstituted: C1-C6 alkylene, C3-C10 cycloalkyl, 4-7 membered heterocyclic alkyl containing 1-3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl. Where R is one of the following groups: C1-C6 alkyl, C3-C10 cycloalkyl, 4-7 membered heterocyclic alkyl containing 1-3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl, and X is O or NR. a ;where R a Selected from: hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl; R 7 The following groups are absent, hydrogen-containing, substituted, or unsubstituted: C1-C6 alkoxy, C3-C10 cycloalkyl, C6-C10 aryl, 3-7 membered heterocyclic, 5-7 membered heteroaryl. Where R is one of the following groups: C1-C6 alkyl, C3-C10 cycloalkyl, 4-7 membered heterocyclic alkyl containing 1-3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl, and X is O or NR. a ;where R a It can be hydrogen, C1-C6 alkyl, or C3-C10 cycloalkyl; L 1 R 7 Substituents spaced 0 to 2 atoms above can cyclize into 3- to 7-membered alkyl rings, 4- to 7-membered heteroalkyl rings, 6-membered aromatic rings, and 5- to 7-membered heteroaromatic rings; The substitution mentioned above refers to the substitution of hydrogen on a group by one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, C1-C6 haloalkyl, alkynyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, NR. d R e , Where R d and R e Each is independently hydrogen or C1-C6 alkyl.

2. The compound according to claim 1, characterized in that, R 1 It can be hydrogen, halogen, cyano, hydroxyl, ethynyl, or C1-C6 alkyl. R 2 It can be hydrogen, halogen, cyano, hydroxyl, ethynyl, C1-C4 alkyl, Where R is a substituted or unsubstituted group of the following: C1-C4 alkyl, and X is O, NR. a ;where R a The group is hydrogen, C1-C4 alkyl, wherein the substitution refers to the substitution of hydrogen on the group by one or more substituents selected from the group consisting of: halogen, hydroxyl, C1-C4 alkyl, NR. d R e , where R d and R e Each is independently hydrogen or C1-C4 alkyl; R 3 Hydrogen, halogen, cyano, hydroxyl, C1-C4 alkyl, Where R is a substituted or unsubstituted group of the following: C1-C4 alkyl, X is O, and wherein the substitution refers to the substitution of a hydrogen atom on the group by one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, C1-C6 alkyl, NR. d R e , where R d and R e Each is independently hydrogen or C1-C4 alkyl; R 4 It can be hydrogen, halogen, cyano, or hydroxyl.

3. The compound according to claim 1, characterized in that, R 5 Hydrogen, C1-C4 alkyl, Where R b The following groups may be substituted or unsubstituted: C1-C4 alkyl, C3-C6 cycloalkyl, C6-C10 aryl, 5-7 heteroaryl, wherein the substitution refers to the substitution of a hydrogen atom on the group by one or more substituents selected from the group consisting of: halogen, hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, NR d R e , where R d and R e Each is independently hydrogen or C1-C4 alkyl; R 6 Hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, Where R b The following groups may be substituted or unsubstituted: C1-C4 alkyl, wherein the substitution refers to the substitution of a hydrogen atom on the group by one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, trifluoromethyl, NR. d R e , where R d and R e Each is independently hydrogen or C1-C4 alkyl.

4. The compound according to claim 1, characterized in that, L 1 The following groups are absent, hydrogen-containing, substituted, or unsubstituted: C1-C4 alkylene, C3-C8 cycloalkyl, 5-7 membered heterocyclic alkyl containing 1-3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl. Where R is one of the following groups: C1-C4 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic alkyl containing 1-3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl, and X is O or NR. a ;where R a The group is hydrogen, C1-C4 alkyl, or C3-C6 cycloalkyl, wherein the substitution refers to the substitution of hydrogen on the group by one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, NR. d R e , where R d and R e Each is independently hydrogen or C1-C4 alkyl.

5. The compound according to claim 1, characterized in that, R 7 The following groups are absent, hydrogen-containing, substituted, or unsubstituted: C1-C4 alkoxy, C3-C6 cycloalkyl, C6-C10 aryl, 5-7 membered heterocyclic, 5-7 membered heteroaryl. Where R is one of the following groups: C1-C6 alkyl, C3-C10 cycloalkyl, 4-7 membered heterocyclic alkyl containing 1-3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl, and X is O or NR. a ;where R a It can be hydrogen, C1-C6 alkyl, or C3-C10 cycloalkyl; R 7 Substituents spaced 0 to 2 atoms above can cyclize into 3- to 7-membered alkyl rings, 4- to 7-membered heteroalkyl rings, 6-membered aromatic rings, and 5- to 7-membered heteroaromatic rings. The substitution mentioned refers to the substitution of hydrogen on a group by one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, C1-C4 haloalkyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, NR. d R e , Where R d and R e Each is independently hydrogen or C1-C4 alkyl; Another preferred option is R 7 The following groups are absent, hydrogen, substituted or unsubstituted: C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, 5-7 membered heterocyclic, 5-7 membered heteroaryl; The substitution mentioned refers to the substitution of a hydrogen atom on a group by one or more substituents selected from the group consisting of: fluorine, chlorine, bromine, hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, alkynyl, C1-C4 alkyl, C1-C4 alkoxy, NR. d R e , Where R d and R e Each is independently hydrogen or C1-C4 alkyl; R 7 Substituents spaced 0 to 2 atoms above can cyclize into a 6-membered aromatic ring or a 5 to 7-membered heteroaromatic ring.

6. The compound according to claim 1, characterized in that, L 1 and R 7 Form the following formula V: Where r1 is selected from 1, 2, or 3; r2 is selected from 0, 1, 2, or 3; Ring B can be phenyl, 5-6 membered heterocyclic, C3-C6 cycloalkyl, or 5-6 membered heteroaryl. Each R f Independently selected from: halogen, hydroxyl, cyano, C1-C4 haloalkyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, NR d R e , Where R d and R e Each is independently hydrogen, C1-C4 alkyl; or two adjacent Rs f Together with the C ring adjacent to ring B, they form a benzene ring and a 5- to 7-membered heteroaryl ring.

7. The compound according to claim 1, characterized in that, The compound is selected from:

8. The method for preparing the compound according to claim 1, characterized in that, The preparation method is as follows Using the same material as a raw material, the compound is obtained by converting the 16-position carboxyl group into an oxadiazole structure, wherein the definitions of each substituent are as described in claim 1.

9. A pharmaceutical composition, characterized in that, Include: The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof; and Pharmaceutically acceptable carrier.

10. Use of the compound of general formula (I) as claimed in claim 1 or the pharmaceutical composition as claimed in claim 9, characterized in that, (i) for the preparation of α2A adrenergic receptor (α2A-AR) antagonists; or (ii) for the preparation of drugs for the treatment of diabetes and diabetic nephropathy.

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