Yohimbine derivative, and preparation method therefor and pharmaceutical composition and use thereof

Abstract

Disclosed in the present invention are a yohimbine derivative, and a preparation method therefor and a pharmaceutical composition and use thereof. The structure of the yohimbine derivative is as shown in formula I, and the definition of each substituent in the formula is as described in the description and the claims. The yohimbine derivative of the present invention is used as an α2A-AR antagonist and can be used for treating diseases such as diabetes and diabetic nephropathy.

Description

Yohimbine derivatives, methods of making, pharmaceutical compositions, and uses thereof 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 method for preparing the same, 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 and is important for regulating catecholamine signaling. Pharmacologically, 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 the former is mainly 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 risk allele rs553668 carriers produce excess α2A-AR in pancreatic beta cells, which inhibits 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 level of insulin release (Science, 2010, 327, 217-220; N. Engl. J. Med., 2010, 362, 361-362). Subsequent studies have confirmed that the α2A-AR antagonist yohimbine can significantly improve the insulin secretion deficiency associated with the ADRA2A risk variant in patients (Sci. Transl. Med., 2014, 6, 257ra139). Since the decrease in the secretion capacity of islet beta cells is one of the main characteristics of T2D, blocking α2A-AR signaling may be a new treatment for the islet 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 is clinically used for the treatment of male erectile dysfunction, and its pharmacokinetics has been well characterized. Common side effects include dizziness, anxiety, restlessness, insomnia, hypertension and palpitations, etc., 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 modified and 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] 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;

[0010] 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;

[0011] 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;

[0012] R7 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;

[0013] L 1 , R 7 Substituents above separated by 0-2 atoms can be annelated to form a 3-7 membered alkyl ring, 4-7 membered heteroalkyl ring, 6 membered aryl ring, 5-7 membered heteroaryl ring;

[0014] The above substituents mean that the hydrogens on the group are replaced by 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.

[0015] In another preferred embodiment, R 1 is hydrogen, halogen, cyano, hydroxyl, ethynyl, C1-C6alkyl;

[0016] 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 by one or more substituents selected from the group consisting of halogen, hydroxyl, C1-C4alkyl, NR d R e wherein R d and R e are each independently hydrogen, C1-C4alkyl;

[0017] R 3 is hydrogen, halogen, cyano, hydroxyl, C1-C4alkyl, wherein R is a substituted or unsubstituted C1-C4 alkyl group, X is O, wherein the substitution means that a hydrogen on the group is replaced by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, C1-C6 alkyl, NR d R e wherein R d and R e are each independently hydrogen, C1-C4 alkyl;

[0018] R 4 is hydrogen, halogen, cyano, hydroxy.

[0019] In another preferred embodiment, R 1 is hydrogen, fluorine.

[0020] In another preferred embodiment, R 2 is hydrogen, fluorine, chlorine, bromine, cyano, hydroxy, ethynyl, methyl, methoxy.

[0021] In another preferred embodiment, R 3 is hydrogen, fluorine, hydroxy, ethynyl, methyl, methoxy.

[0022] In another preferred embodiment, R 4 is hydrogen.

[0023] In another preferred embodiment, R 5 is hydrogen, C1-C4 alkyl, wherein R b is a substituted or unsubstituted C1-C4 alkyl group, C3-C6 cycloalkyl group, C6-C10 aryl group, 5-7 membered heteroaryl group, wherein the substitution means that a hydrogen on the group is replaced by one or more substituents selected from the group consisting of halogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, NR d R e wherein R d and R e are each independently hydrogen, C1-C4 alkyl;

[0024] R 6 is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, wherein R b is a substituted or unsubstituted C1-C4 alkyl group, wherein the substitution means that a hydrogen on the group is replaced by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, trifluoromethyl, NR d R e wherein R d and R e are each independently hydrogen, C1-C4 alkyl.

[0025] In another preferred embodiment, R 5hydrogen, C1-C3 alkyl, acetyl.

[0026] In another preferred embodiment, R 6 hydrogen, C1-C3 alkyl, acetyl.

[0027] In another preferred embodiment, L 1 is absent, hydrogen, substituted or unsubstituted C1-C4 alkylene, C3-C8 cycloalkyl, 5-7 membered heterocycloalkyl with 1 to 3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl, wherein R is C1-C4 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocycloalkyl with 1 to 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.

[0028] In another preferred embodiment, L 1 is absent, hydrogen, substituted or unsubstituted C1-C4 alkylene, C3-C6 cycloalkyl, 5-7 membered heterocycloalkyl with 1 to 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.

[0029] 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 to 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;

[0030] R7 The 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,

[0031] wherein the substitution means that a hydrogen on the group is replaced by one or more substituents 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.

[0032] 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;

[0033] wherein the substitution means that a hydrogen on the group is replaced by one or more substituents selected from the group consisting of fluorine, chlorine, bromine, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, alkynyl, C1-C4alkyl, C1-C4alkoxy, wherein R d and R e are each independently hydrogen, C1-C4alkyl;

[0034] 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.

[0035] In another preferred embodiment, L 1 and R 7 are of formula V:

[0036] wherein r1 is selected from 1, 2 or 3; r2 is selected from 0, 1, 2 or 3;

[0037] Ring B is phenyl, 5- to 6-membered heterocyclyl, C3-C6cycloalkyl, 5- to 6-membered heteroaryl;

[0038] Each R f 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

[0039] two R f form, together with the adjacent C on ring B, a phenyl ring, a 5- to 7-membered heteroaromatic ring.

[0040] In another preferred embodiment, ring B is a phenyl ring, and the substituents thereon are located in the para position relative to L 1 .

[0041] In another preferred embodiment, the compound of formula V has the following structure:

[0042] wherein r1 is selected from 1, 2 or 3; r2 is selected from 0, 1, 2 or 3;

[0043] Z1, Z2, Z3 are each independently selected from O, S, N, CH;

[0044] 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

[0045] 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.

[0046] In another preferred embodiment, r2 is selected from 1 or 2.

[0047] In another preferred embodiment, Z1, Z2, Z3 are each independently selected from O, N, CH.

[0048] 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

[0049] two R f form, together with the adjacent C on the ring, a phenyl ring.

[0050] In another preferred embodiment, -L 1 -R 7 is selected from:

[0051] The number of substituents Rf on the phenyl ring or benzo-heteroaryl ring is 0, 1, 2 or 3, preferably 0, 1 or 2.

[0052] In another preferred embodiment, -L 1 -R 7 is selected from the group consisting of: -CH3,

[0053] In another preferred embodiment, the compound is selected from C1-C35.

[0054] In a second aspect of the present application, there is provided a process for preparing a compound of the first aspect, by converting the carboxyl group at position 16 into an oxadiazole structure, using a compound of formula (I) as starting material, wherein the substituents are as defined above.

[0055] In a preferred embodiment, the compound or pharmaceutically acceptable salt thereof is prepared by the following route:

[0056] The compound of formula H1 is reacted with a compound of formula H2 under condensing agent conditions to give a compound of formula H3;

[0057] The compound of formula H3 is subjected to intramolecular condensation cyclization under heating conditions to give a compound of formula H4;

[0058] 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;

[0059] 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 ;

[0060] 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 carboxyl;

[0061] wherein the substituents are as defined above.

[0062] ​In a third aspect, the present application provides a pharmaceutical composition comprising: the compound of general formula (I) or a pharmaceutically acceptable salt thereof according to the first aspect; and a pharmaceutically acceptable carrier.

[0063] In a fourth aspect, the present application provides the use of the compound of general formula (I) according to the first aspect or the pharmaceutical composition according to 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.

[0064] In a fifth aspect, the present application provides a method for treating diabetes and diabetic nephropathy, comprising administering to a subject in need thereof the compound of the first aspect or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the third aspect.

[0065] The novel oxadiazole-based yohimbine derivatives of the present application can antagonize alpha2A adrenergic receptors at micromolar concentrations, and have the characteristics of kidney and pancreas targeting and significantly reduced brain tissue distribution characteristics relative to yohimbine.

[0066] 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 below (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

[0067] Figure 1 shows the tissue concentration (ng / g or ng / mL) of different compounds after intragastrically administering 10 mg / kg to mice for 2 h.

[0068] Figure 2 shows the tissue concentration (ng / g or ng / mL) of compound C27 after intragastrically administering 10 mg / kg to mice for 0.25, 2, and 8 h.

[0069] Figure 3 shows the basal blood glucose level of type 2 diabetic mice after a single intraperitoneal injection of yohimbine derivatives (10 mg / kg).

[0070] Figure 4 shows the glucose tolerance results of type 2 diabetic mice after a single intraperitoneal injection of yohimbine derivatives (10 mg / kg).

[0071] Figure 5 shows the insulin sensitivity results of type 2 diabetic mice after a single intraperitoneal injection of yohimbine derivatives (10 mg / kg).

[0072] Figure 6 shows the glucose tolerance results of type 2 diabetic mice after a single intragastric administration of yohimbine derivatives (10 mg / kg).

[0073] Figure 7 shows the results of insulin sensitivity of the diabetic mice after a single gavage of yohimbine derivative (10 mg / kg).

[0074] Figure 8 shows the results of basal blood glucose levels of the diabetic mice after chronic injection of yohimbine derivative (10 mg / kg, once a day).

[0075] Figure 9 shows the results of the effect of chronic administration of yohimbine derivative C27 on random blood glucose of diabetic BTBR ob / ob mice.

[0076] Figure 10 shows the results of the effect of chronic administration of yohimbine derivative C27 on urine volume of diabetic BTBR ob / ob mice.

[0077] Figure 11 shows the results of the effect of chronic administration of yohimbine derivative C27 on urinary albumin excretion of diabetic BTBR ob / ob mice.

[0078] Figure 12 shows the results of the effect of chronic administration of yohimbine derivative C27 on urinary albumin creatinine ratio of diabetic BTBR ob / ob mice. DETAILED DESCRIPTION

[0079] The inventors of the present application have made extensive and in-depth research and for the first time developed a class of compounds with pancreatic targeting and low brain permeability while maintaining good α2A adrenergic receptor antagonistic activity, specifically, a class of oxadiazole yohimbine derivatives, which are mainly characterized by converting the ester group at position 16 of yohimbine into an oxadiazole group, which can maintain good α2A adrenergic receptor antagonistic activity. Compared with yohimbine, the derivatives of this class have the characteristics of kidney and pancreatic targeting and significantly reduced brain tissue distribution characteristics relative to yohimbine, eliminating the central side effects of yohimbine such as anxiety and elevated blood pressure, and can significantly improve the blood glucose metabolism and kidney function of animal models of type 2 diabetes, and are expected to become a new type of drug for treating diabetes and diabetic nephropathy by acting on α2A adrenergic receptors. On this basis, the present application is completed.

[0080] TERMS

[0081] In the present text, the alkyl groups are preferably aliphatic alkyl groups, which can be linear or branched, and include, without limitation, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, and the like; the expression "C1-C6", for example, is intended to include the respective groups having 1, 2, 3, 4, 5, or 6 carbon atoms, for example, "C1-C6 alkyl" means an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms.

[0082] "Alkylene" refers to a straight-chained or branched saturated aliphatic radical of the indicated number of carbon atoms and bonds that links at least two other groups, i.e., a divalent hydrocarbon radical. The two groups attached to the alkylene can be attached to the same or different atoms on the alkylene. For example, a straight-chained alkylene can be a divalent radical 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.

[0083] As used herein, the term "halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0084] As used herein, the term "alkoxy" refers to -O-(alkyl), where alkyl is as defined above. "C1-C6alkoxy" refers to an oxygen-containing alkyl group containing 1 to 6 carbons, non-limiting examples of which include methoxy, ethoxy, propoxy, butoxy, and the like.

[0085] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent including 3 to 20 carbon atoms, preferably including 3 to 12 carbon atoms, more preferably the cycloalkyl group includes 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.

[0086] 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) groups, and the group has a conjugated pi-electron system, for example, phenyl and naphthyl. The aryl ring can be fused to a heterocyclyl, heteroaryl, or cycloalkyl ring, non-limiting examples of which include benzimidazole, benzothiazole, benzoxazole, benzisoxazole, benzopyrazole, quinoline, benzoindole, benzodihydrofuran.

[0087] As used herein, the term "heterocyclyl" refers to a saturated or partially unsaturated aliphatic ring system containing 1 to 3 heteroatoms, such as 3 to 7 ring atoms. The heteroatoms of a heterocyclyl group include oxygen, sulfur, and nitrogen. Heterocyclyl groups are preferably 3- or 6-membered, for example, oxiranyl, morpholinyl, piperazinyl, and the like.

[0088] As used herein, the term "heteroaryl" refers to a heteroaromatic ring system containing 1 to 4 heteroatoms, such as 5 to 14 ring atoms. The heteroatoms of a heteroaryl group include oxygen, sulfur, and nitrogen. Heteroaryl groups are preferably 5- or 6-membered, for example, furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl group can be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring that is attached to the parent structure is the heteroaryl ring.

[0089] In the present application, unless otherwise indicated, represents the point of attachment.

[0090] The pharmaceutically acceptable salt is not particularly limited herein, and preferably includes inorganic acid salts, organic acid salts, alkyl sulfonic acid salts, and aryl sulfonic 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 alkyl sulfonic acid salts include methanesulfonates, ethanesulfonates, and the like; and the aryl sulfonic acid salts include benzenesulfonates, p-toluenesulfonates, and the like.

[0091] Preparation method

[0092] 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.

[0093] The present application will be further described in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present application and not intended to limit the scope of the present application. The experimental methods in the following examples, for which no specific conditions are indicated, are generally performed according to the conventional conditions or according to the conditions suggested by the manufacturers. Unless otherwise specified, the percentages and parts are weight percentages and weight parts.

[0094] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. In addition, any method and material similar or equivalent to those described herein can be used in the practice of the present application. The described preferred methods and materials are only examples.

[0095] 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 silica gel plates were produced by Yantai Jiangyou Silica Gel Development Co., Ltd., model HSGF 254; normal phase column chromatography silica gel used for purification of compounds was produced by Qingdao Haizhuan Chemical Factory Branch, model zcx-II, 200-300 mesh.

[0096] The Chinese corresponding to the abbreviations used herein are as follows:

[0097] 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;

[0098] Example 1

[0099] (1) At room temperature, 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 successively. After stirring 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 the organic phase was dried over anhydrous sodium sulfate. After reduced pressure concentration, the product was used directly in the condensation reaction without purification.

[0100] (2) Under ice-bath, yohimbine Ml hydrochloride (7.81 g, 20 mmol) was dissolved in methanol / tetrahydrofuran / water (90 mL / 60 mL / 30 mL), and lithium hydroxide monohydrate (5.04 g, 120 mmol) was added. After stirring for half an hour under ice-bath, the reaction was moved to room temperature. After LC-MS monitoring 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 appearance of milky turbidity by 5% hydrochloric acid under ice-bath. After standing overnight, the product was filtered and washed with water (100 mL). The collected filter cake was dried to obtain white powder M2 (5.9 g, 17.3 mmol) with a molar yield of 86%.

[0101] (3) At room temperature, M2 (340 mg, 1 mmol) was dissolved in DMF (5 mL), and triethylamine (304 mg, 3 mmol) was added. After stirring for 5 minutes, COMU (428 mg, 1 mmol) was slowly added. After stirring at room temperature for 20 minutes, the crude product in (1) (300 mg, 2 mmol) was added. After stirring at room temperature for 24 hours, the reaction solution was concentrated by 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), and the organic phase was dried over anhydrous sodium sulfate. After reduced pressure concentration, column chromatography purification (dichloromethane / methanol = 30:1) was performed to obtain brown foam solid M3.

[0102] (4) The condensation product M3 in (3) was dissolved in 1,4-dioxane (5 mL), and toluene (10 mL) was added. After heating to 100°C under 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 the organic phase was dried over anhydrous sodium sulfate. After reduced pressure concentration, column chromatography purification (dichloromethane / methanol = 30:1) was performed to obtain light brown foam solid C1 (46 mg, 0.1 mmol) with a molar yield of 10% for two steps of (3) and (4).

[0103] The following compounds in the table below were synthesized using the same procedure as in Example 1 with different cyano substrates:

[0104] Example 2

[0105] (1) 4-Iodobenzeneacetonitrile (2.43 g, 10 mmol) was dissolved in ethanol (20 mL) at room temperature, and water (8 mL), sodium carbonate (848 mg, 8 mmol), and hydroxylamine hydrochloride (695 mg, 10 mmol) were added successively. The mixture was stirred at room temperature for 24 hours, and 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, and the product was used directly in the condensation reaction without purification.

[0106] (2) M2 (340 mg, 1 mmol) was dissolved in DMF (5 mL) at room temperature, and triethylamine (304 mg, 3 mmol) was added. After stirring for 5 minutes, COMU (428 mg, 1 mmol) was slowly added, and the mixture was stirred at room temperature for 20 minutes. Then, the crude product from operation (1) (552 mg, 2 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was dissolved in dichloromethane / methanol (100 mL / 10 mL). The solution was washed with saturated brine (20 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and column chromatography was performed using dichloromethane / methanol (30:1) to obtain M3 as a brownish foam.

[0107] (3) The condensation product M3 from operation (2) was dissolved in 1,4-dioxane (5 mL), and toluene (10 mL) was added. The mixture was heated to 100°C under a nitrogen atmosphere, and the reaction was stopped after 24 hours. The solvent was removed by reduced pressure concentration, and the residue was dissolved in dichloromethane / methanol (100 mL / 10 mL). The solution was washed with saturated brine (20 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and column chromatography was performed using dichloromethane / methanol (30:1) to obtain M4 as a light brownish foam (69 mg, 0.12 mmol). The two-step molar yield of operations (2) and (3) was 12%.

[0108] (4) Compound M4 (58 mg, 0.1 mmol) was dissolved in DMF (5 mL), and Pd(dba)2(5.7 mg, 0.01 mmol), dppf (5.5 mg, 0.01 mmol), Zn(CN)2(11.7 mg, 0.1 mmol) were added. The reaction mixture was heated to 80 °C under nitrogen atmosphere. After 6 hours, the reaction was stopped, and 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 the organic phase was dried over anhydrous sodium sulfate. The solvent was removed by reduced pressure concentration, and the residue was purified by column chromatography (dichloromethane / methanol = 30:1) to give compound C19 (33 mg, 0.07 mmol) as a light brown foamy solid with a 70% molar yield.

[0109] Other compounds in the following table were synthesized using the same method as in Example 2 with different cyano substrates:

[0110] Example 3

[0111] Compound C19 (14 mg, 0.03 mmol) was dissolved in EtOH (0.15 mL), and DMSO (0.075 mL) was added under ice bath. Then 4 M NaOH (0.0073 mL) and 30% H2O2(0.01 mL) were added. After 30 minutes of reaction under ice bath, the reaction mixture was moved to room temperature. After 5 hours, the reaction was stopped, and 10% Na2S2O3(0.15 mL) was added to the reaction mixture under ice bath. Then H2O (2 mL) was added, and a white solid was precipitated. The solid was filtered under reduced pressure, washed with water, and dried to give compound C27 (10 mg, 0.02 mmol) as a white solid with a 67% molar yield.

[0112] Example 4

[0113] Compound C29 (50 mg, 0.1 mmol) was dissolved in methanol / tetrahydrofuran / water (2.1 mL / 0.3 mL / 0.6 mL) under ice bath, and lithium hydroxide monohydrate (42 mg, 1 mmol) was added. After stirring for half an hour under ice bath, the reaction mixture was moved to room temperature. The reaction was monitored by LC-MS until the starting material was consumed. Most of the solvent was removed by reduced pressure concentration, and the residue was added with water (5 mL). The pH was adjusted to about 6 with 5% hydrochloric acid under ice bath. The mixture was left to stand, and the solid was filtered. The filter cake was washed with water (2 mL), and the filter cake was collected and dried to give compound C30 (25 mg, 0.05 mmol) as a yellow powder with a 50% molar yield.

[0114] Example 5 α2A-AR antagonist test

[0115] 1. Purpose of experiment

[0116] To investigate the antagonistic activity of yohimbine derivatives on α2A-AR.

[0117] 2. Experimental principle

[0118] By establishing a cell line co-transfected with 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 to detect 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 cellular 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.

[0119] 3. Experimental samples

[0120] Before the test, the test compound is dissolved in DMSO to prepare a mother liquor, which is diluted with culture solution to the required concentration for use.

[0121] 4. Experimental method

[0122] The cells stably expressing α2A-AR / Ga16 are seeded in a 96-well plate and cultured overnight; the culture solution in the wells 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 washed with fresh calcium buffer, and then 50 μL of calcium buffer dissolved with the test drug is added; the FlexStation II instrument is used for detection, and 25 μL of calcium buffer dissolved with the known agonist UK14304 is automatically added by the instrument starting from the 15th second, and the fluorescence value at 525 nm is finally read.

[0123] 5. Experimental results (taking 35 compounds in Table 1 as an example, but not limited to these compounds)

[0124] Table 1 Test results of α2A-AR antagonistic activity of compounds Note: IC 50 is the evaluation of the antagonistic activity of the sample drug on α2A-AR. * represents 0.5 μM≤IC 50 <2 μM; ** represents 0.3 μM≤IC50 <0.5μM, *** represents 0.1μM≤IC 50 <0.3μM; **** represents IC 50 <0.1μM.

[0125] 6. Results and Discussion

[0126] These compounds were able to compete with the α2A-AR agonist UK14304 in cells expressing α2A-AR and antagonize the α2A-AR agonistic effect of UK14304, IC50 50 See Table 1. The results indicate that these compounds are antagonists of α2A-AR.

[0127] Example 6: Distribution assay of yohimbine derivatives in mouse tissues

[0128] 1. Experimental Objective

[0129] The tissue distribution of yohimbine derivatives in mice was investigated.

[0130] 2. Experimental Design

[0131] Table 2 Dosage regimens for mouse tissue distribution assay Note: All administered compounds were in hydrochloride form and prepared with deionized water; all test animals were male ICR animals.

[0132] Mice were fasted for more than 12 hours but given free access to water.

[0133] Table 3. Experimental protocol for the distribution of compound C27 in mouse tissues. Note: The solvent ratio was 5% DMSO + 5% solubilol + 90% saline; all experimental animals were male ICR.

[0134] Mice were fasted for more than 12 hours but given free access to water.

[0135] 3. Sample collection and measurement

[0136] (1) Mouse tissue distribution test: Animals in each group were euthanized 2 hours after administration, and brain, pancreas, heart, liver and kidney tissues were collected by dissection. After washing with physiological saline, the tissues were frozen and stored at -20℃ for later testing. At the same time, 0.3 mL of whole blood was collected into EDTA-K2 anticoagulant tubes, and plasma was separated by centrifugation at 11000 rpm for 5 min. The plasma was frozen and stored at -20℃ for later testing.

[0137] Blank plasma and tissue were collected from three other animals.

[0138] The concentration of the parent drug in plasma and tissues was determined.

[0139] (2) Compound C27 mouse tissue distribution test: After intragastric administration, the mice were sacrificed by abdominal aortic exsanguination at the corresponding time points (0.25, 2 and 8 h), and the brain, heart, liver, lung, pancreas, kidney tissues were immediately dissected and collected, and part of the plasma was collected. Ice water bath operation.

[0140] Centrifugal conditions: 11000 rpm centrifugation for 5 min, separation of plasma (about 200 μL).

[0141] After the collection of tissues and plasma, store below -60°C.

[0142] 4. Experimental results and discussion

[0143] Figure 1 shows the tissue concentration (ng / g or ng / mL) of different compounds in mice after intragastric administration of 10 mg / kg for 2 h. (Taking the four compounds in Figure 1 as an example, but not limited to these compounds)

[0144] Figure 2 shows the tissue concentration (ng / g or ng / mL) of compound C27 in mice after intragastric administration of 10 mg / kg at 0.25, 2 and 8 h.

[0145] Calculated by the relative ratio of tissue distribution concentration to blood concentration, compounds C1, C6, C13, C19 and C27 all show lower brain tissue distribution than yohimbine, among which the brain tissue distribution of compound C19 is about forty times lower than yohimbine, and compound C19 also has good pancreas distribution; the plasma exposure of compound C27 is comparable to yohimbine, but its brain tissue distribution is about two hundred and seventy times lower than yohimbine, and has pancreas distribution characteristics comparable to compound C19.

[0146] Example 7 Test experiment of yohimbine derivative on the treatment effect of reducing blood sugar in diabetic mice

[0147] 1. Purpose of the experiment

[0148] To test whether yohimbine derivative C19 can improve the blood sugar metabolism of type 2 diabetes

[0149] 2. Experimental content

[0150] This experiment uses a type 2 diabetes mouse model induced by high-sugar high-fat diet, and mainly tests the following aspects:

[0151] 1) The effect of single intraperitoneal administration on the basal blood glucose, glucose tolerance and insulin sensitivity of diabetic mice.

[0152] 2) The effect of single intragastric administration on the glucose tolerance and insulin sensitivity of diabetic mice.

[0153] 3) The effect of continuous chronic intraperitoneal administration on the basal blood glucose of diabetic mice.

[0154] 3. Experimental Methods

[0155] C57BL\6J mice were continuously fed with high sugar and high fat diet for 3 months. After the average weight of the mice was stabilized at more than 50 g and the average basal blood glucose value was stabilized at more than 12 mmol / L, the test experiment was performed.

[0156] The blood glucose level was mainly determined by measuring the tail vein blood using a blood glucose meter. For the test of the effect on basal blood glucose, the basal blood glucose value before administration was first determined under normal diet of the mice, and then the yohimbine derivative C19 (10 mg / kg of mouse weight) was administered by single intraperitoneal injection or single gavage, and the blood glucose level of the vein blood was determined in turn at 15, 30, 60, 90 and 120 minutes after administration. The test of glucose tolerance of the mice was performed after the mice had been fed overnight for 16 hours. After 30 minutes of single intraperitoneal injection or single gavage administration of the yohimbine derivative C19 (10 mg / kg of mouse weight), glucose (1.5 g / kg) was injected intraperitoneally, and the blood glucose level of the vein blood was determined in turn at 15, 30, 60, 90 and 120 minutes after administration. The insulin sensitivity of the mice was performed after the mice had been fed for 6 hours. After 30 minutes of single intraperitoneal injection or single gavage administration of the yohimbine derivative C19 (10 mg / kg of mouse weight), insulin (1 UI / kg) was injected intraperitoneally, and the blood glucose level of the vein blood was determined in turn at 15, 30, 60, 90 and 120 minutes after administration. For the experiment of the effect of chronic administration on the blood glucose level, the yohimbine derivative C19 (10 mg / kg) was injected intraperitoneally to the diabetic mice every day for 12 consecutive days, and the basal blood glucose level of the mice under free diet was determined every day before the drug injection. The control group was injected with normal saline or gavaged with the drug.

[0157] 4. Experimental Results

[0158] The experimental results are shown in Figures 3-8. Figure 3 shows that single intraperitoneal injection of the yohimbine derivative (10 mg / kg) significantly reduces the basal blood glucose level of the type 2 diabetic mice. Figure 4 shows that single intraperitoneal injection of the yohimbine derivative (10 mg / kg) significantly improves the glucose tolerance of the type 2 diabetic mice. Figure 5 shows that single intraperitoneal injection of the yohimbine derivative (10 mg / kg) significantly improves the insulin sensitivity of the type 2 diabetic mice. Figure 6 shows that single gavage administration of the yohimbine derivative (10 mg / kg) significantly improves the glucose tolerance of the type 2 diabetic mice. Figure 7 shows that single gavage administration of the yohimbine derivative (10 mg / kg) significantly improves the insulin sensitivity of the type 2 diabetic mice. Figure 8 shows that chronic injection of the yohimbine derivative (10 mg / kg, once a day) significantly reduces the basal blood glucose level of the type 2 diabetic mice.

[0159] 5. Results and Discussion

[0160] The experiment shows that single injection or oral administration of the yohimbine derivative C19 of the present application can significantly reduce the high blood sugar level of diabetic mice, and can improve glucose tolerance and increase insulin sensitivity. Chronic administration can maintain the basal blood sugar level of diabetic mice at a more normal level. Therefore, the yohimbine derivative C19 of the present application has a significant effect on improving blood sugar metabolism in diabetes.

[0161] Example 8 Evaluation of the therapeutic effect of yohimbine derivative C27 on diabetic nephropathy

[0162] 1. Purpose of the experiment

[0163] To investigate the improvement of diabetic nephropathy in BTBR ob / ob mice by long-term administration of yohimbine derivative C27.

[0164] 2. Experimental design

[0165] 38 BTBR ob / ob mice (24 males and 24 females) were brought into the animal house at 5 weeks of age and raised until they were 7 weeks old. Ten days before administration, all BTBR ob / ob mice were collected for 6 hours of urine, urine volume was recorded, and urine microalbumin and creatinine levels were detected. Two days before administration, random blood glucose and body weight were measured in the morning, 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 males and 6 females). They were the model control group, yohimbine derivative C27 1, 3 and 10 mg / kg dose groups, and a group of BTBR ob / ob mice from the same litter as the normal control. Oral gavage administration, the volume of administration was 10 ml / kg, once a day.

[0166] 3. Index detection

[0167] The normal control group, model control group, each administration group and positive control group of mice were detected for blood glucose every 2 weeks after the first administration; urine was collected every 4 weeks to detect urine volume, urine microalbumin and creatinine levels, and urine microalbumin excretion and microalbumin creatinine ratio were calculated.

[0168] 4. Experimental results

[0169] (1). The effect of long-term administration of yohimbine derivative C27 on blood glucose in diabetic BTBR ob / ob mice

[0170] Figure 9 shows the effect of chronic administration of yohimbine derivative C27 on random blood glucose in diabetic BTBR ob / ob mice, where *p<0.05, compared with the model group; **p<0.01, compared with the model control group.

[0171] Figure 9 shows 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 remained at a relatively stable level. Chronic administration of yohimbine derivative C27 for 6 weeks significantly reduced the random blood glucose of diabetic BTBR ob / ob mice, and the effect lasted until the end of administration. Thus, yohimbine derivative C27 can dose-dependently reduce the random blood glucose of diabetic BTBR ob / ob mice.

[0172] (2). Effect of long-term administration of yohimbine derivative C27 on urine volume of diabetic BTBR ob / ob mice

[0173] Figure 10 shows the effect of chronic administration of yohimbine derivative C27 on urine volume of diabetic BTBR ob / ob mice, where *p<0.05, compared with the model group; **p<0.01, compared with the model control group.

[0174] Figure 10 shows that the urine volume of the model control group of diabetic BTBR ob / ob mice was always significantly higher than that of the normal control group during the test period. Chronic administration of yohimbine derivative C27 for 4 weeks dose-dependently reduced the urine volume of diabetic BTBR ob / ob mice, and the effect lasted until administration for 8 weeks. Thus, yohimbine derivative C27 can dose-dependently reduce the urine volume of diabetic nephropathy mice.

[0175] (3). Effect of long-term administration of yohimbine derivative C27 on urinary microalbumin of diabetic BTBR ob / ob mice

[0176] Figure 11 shows the effect of chronic administration of yohimbine derivative C27 on urinary microalbumin excretion of diabetic BTBR ob / ob mice, where *p<0.05, compared with the model group; **p<0.01, compared with the model control group.

[0177] Figure 11 shows 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 dose-dependently reduced the urinary microalbumin excretion of diabetic BTBR ob / ob mice, and the effect lasted until administration for 8 weeks. Thus, chronic administration of yohimbine derivative C27 can significantly improve the urinary microalbumin excretion of diabetic nephropathy mice.

[0178] (4). Effect of long-term administration of yohimbine derivative C27 on urinary microalbumin creatinine ratio of diabetic BTBR ob / ob mice

[0179] Figure 12 is a result of the influence of chronic administration of yohimbine derivative C27 on urine 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.

[0180] Figure 12 shows that the urine microalbumin creatinine ratio of the model control group of diabetic BTBR ob / ob mice is significantly higher than that of the normal control group during the experiment. Chronic administration of yohimbine derivative C27 for 4 weeks can dose-dependently reduce the urine microalbumin creatinine ratio of diabetic BTBR ob / ob mice, and the effect lasts until administration for 8 weeks. Thus, it is shown that chronic administration of yohimbine derivative C27 can significantly improve diabetic nephropathy.

[0181] 5Results and Discussion

[0182] The experiment shows that chronic gavage administration of yohimbine derivative C27 of the present application can significantly reduce the blood glucose, urine volume, urine microalbumin excretion and urine microalbumin creatinine ratio of diabetic BTBR ob / ob mice. Therefore, yohimbine derivative C27 of the present application has a significant effect of improving diabetic nephropathy.

[0183] Through structural modification of yohimbine, a new derivative with improved α2A adrenergic receptor antagonistic activity, pancreatic and kidney targeting and reduced brain tissue distribution is obtained. The lower brain tissue distribution eliminates the central side effects of yohimbine such as anxiety and elevated blood pressure. The compound of the present application can significantly improve blood glucose metabolism in a type 2 diabetes animal model. Chronic administration can stabilize the basal blood glucose level of diabetic mice, and further improve the urine volume, urine microalbumin excretion and urine microalbumin creatinine ratio of diabetic mice, and is expected to be used for the treatment of diabetes and diabetic nephropathy.

[0184] All the documents mentioned in the present 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 those skilled in the art can make various modifications or amendments to the present application after reading the above teachings of the present application, and these equivalent forms also fall within the scope defined by the claims attached to the present application.

Claims

1. A compound represented by the general formula (I), a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, halogen, cyano, hydroxyl, ethynyl, substituted or unsubstituted C1-C6alkyl, C3-C10cycloalkyl, 4-7 membered heterocycloalkyl containing from 1 to 3 heteroatoms, C6-C10aryl, 5-7 membered heteroaryl, wherein R is a group selected from: C1-C6alkyl, C3-C10cycloalkyl, 4-7 membered heterocycloalkyl containing 1 to 3 heteroatoms, C6-C10aryl, 5-7 membered heteroaryl, X is O or NR a ; wherein R a is selected from: hydrogen, C1-C6alkyl, C3-C10cycloalkyl; R 5 and R 6 each independently is hydrogen, a substituted or unsubstituted group: C1-C6alkyl, C3-C10cycloalkyl, 4-7 membered heterocycloalkyl containing from 1 to 3 heteroatoms, wherein R b is selected from the group consisting of: C1-C6alkyl, C3-C10cycloalkyl, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, C6-C10aryl, 5-7 membered heteroaryl, X is O or NR c ; wherein R c is selected from the group consisting of: hydrogen, C1-C6alkyl, C3-C10cycloalkyl; L 1 is absent, hydrogen, a substituted or unsubstituted group selected from the group consisting of C1-C6alkylene, C3-C10cycloalkyl, 4-7 membered heterocycloalkyl containing from 1 to 3 heteroatoms, C6-C10aryl, 5-7 membered heteroaryl, wherein R is a group selected from: C1-C6alkyl, C3-C10cycloalkyl, 4-7 membered heterocycloalkyl containing 1 to 3 heteroatoms, C6-C10aryl, 5-7 membered heteroaryl, X is O or NR a ; wherein R a is selected from: hydrogen, C1-C6alkyl, C3-C10cycloalkyl; R 7 is absent, hydrogen, a substituted or unsubstituted group selected from the group consisting of C1-C6alkoxy, C3-C10cycloalkyl, C6-C10aryl, 3-7 membered heterocyclyl, 5-7 membered heteroaryl, wherein R is a group selected from C1-C6alkyl, C3-C10cycloalkyl, 4-7 membered heterocycloalkyl containing 1 to 3 heteroatoms, C6-C10aryl, 5-7 membered heteroaryl, X is O or NR a ; wherein R a is hydrogen, C1-C6alkyl, C3-C10cycloalkyl; L 1 、R 7 The substituent group spaced 0-2 atoms above can be annelated to a 3-7 membered alkyl ring, 4-7 membered heteroalkyl ring, 6 membered aromatic ring, 5-7 membered heteroaromatic ring; The above-mentioned substitutions mean that a hydrogen on a group is replaced by one or more substituents selected from the group consisting of halogen, hydroxyl, cyano, C1-C6haloalkyl, alkynyl, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkoxy, NR d R e 、 wherein R d and R e each independently is hydrogen, Ci-C6alkyl.

2. The compound of claim 1, wherein R 1 is hydrogen, halogen, cyano, hydroxy, ethynyl, Ci-C6alkyl; R 2 halogen, cyano, hydroxy, ethynyl, C1-C4-alkyl, wherein R is a substituted or unsubstituted group: C1-C4alkyl, X is O, NR a ; wherein R a is hydrogen, C1-C4alkyl, wherein the substitution means that a hydrogen on the group is replaced by one or more substituents selected from the group consisting of: halo, hydroxyl, C1-C4alkyl, NR d R e , wherein R d and R e are each independently hydrogen, C1-C4alkyl; R 3 halogen, cyano, hydroxy, C1-C4-alkyl, wherein R is a substituted or unsubstituted group: C1-C4alkyl, X is O, wherein the substitution means that a hydrogen on the group is replaced with one or more substituents selected from the group consisting of: halo, hydroxyl, cyano, C1-C6alkyl, NR d R e wherein R d and R e each independently is hydrogen, C1-C4alkyl; R 4 is hydrogen, halogen, cyano, hydroxy.

3. The compound of claim 1, wherein R 5 is hydrogen, C1-C4alkyl, wherein R b is a substituted or unsubstituted group selected from the group consisting of C1-C4alkyl, C3-C6cycloalkyl, C6-C10aryl, 5-7 membered heteroaryl, 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, C1-C4alkyl, C1-C4alkoxy, NR d R e wherein R d and R e are each independently hydrogen, C1-C4alkyl; R 6 is hydrogen, C1-C4alkyl, C3-C6cycloalkyl, wherein R b is a substituted or unsubstituted group selected from the group consisting of C1-C4alkyl, wherein the substitution means that a hydrogen on the group is replaced with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, trifluoromethyl, NR d R e , wherein R d and R e are each independently hydrogen, C1-C4alkyl.

4. The compound of claim 1, wherein L 1 is absent, hydrogen, a substituted or unsubstituted group selected from the group consisting of C1-C4 alkylene, C3-C8 cycloalkyl, 5-7 membered heterocycloalkyl containing from 1 to 3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl, wherein R is a group selected from the group consisting of C1-C4 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocycloalkyl containing from 1 to 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, hydroxy, 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.

5. The compound of claim 1, wherein R 7 is absent, hydrogen, a substituted or unsubstituted group selected from the group consisting of C1-C4alkoxy, C3-C6cycloalkyl, C6-C10aryl, 5-7 membered heterocyclyl, 5-7 membered heteroaryl, wherein R is a group selected from the group consisting of 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; R 7 Substituents spaced 0-2 atoms apart can cyclize to form a 3-7 membered alkyl ring, 4-7 membered heteroalkyl ring, 6 membered aromatic ring, 5-7 membered heteroaromatic ring, wherein the substituents are one or more substituents 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 each independently is hydrogen, C1-C4alkyl; Another preferred, R 7 is absent, hydrogen, a substituted or unsubstituted group: C1-C4alkoxy, C3-C6cycloalkyl, phenyl, 5-7 membered heterocyclyl, 5-7 membered heteroaryl; wherein the substituents are one or more substituents selected from the group consisting of fluorine, chlorine, bromine, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, alkynyl, C1-C4alkyl, C1-C4alkoxy, NR d R e 、 wherein R d and R e each independently is hydrogen, C1-C4alkyl; R 7 The substituents spaced apart by 0 to 2 atoms can be annelated to a 6-membered aromatic ring or a 5- to 7-membered heteroaromatic ring.

6. The compound of claim 1, wherein L 1 and R 7 constitute the following formula V: wherein r1 is selected from 1, 2, or 3; r2 is selected from 0, 1, 2, or 3; Ring B is phenyl, 5-6 membered heterocyclyl, C3-C6 cycloalkyl, 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 , wherein R d and R e each independently is hydrogen, C1-C4alkyl; or two adjacent R f form together with the adjacent C on ring B a benzene ring, a 5-7 membered heteroaromatic ring.

7. The compound of claim 1, wherein The compound is selected from:

8. The method for preparing the compound according to claim 1, characterized in that, The production method uses as a starting material, and the compound is obtained by converting the carboxyl group at the 16-position into an oxadiazole structure, wherein the definitions of the substituents are as described in claim 1.

9. A pharmaceutical composition, characterized by, comprising: a compound of Formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

10. The compound of general formula (I) according to claim 1 or the pharmaceutical composition for use according to claim 9, wherein, (i) for use in the manufacture of an alpha2A adrenergic receptor (alpha2A-AR) antagonist; or (ii) for use in the manufacture of a medicament for the treatment of diabetes and diabetic nephropathy.

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