CN111423396B - sEH inhibitor, and preparation method and application thereof - Google Patents

sEH inhibitor, and preparation method and application thereof Download PDF

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CN111423396B
CN111423396B CN202010363513.4A CN202010363513A CN111423396B CN 111423396 B CN111423396 B CN 111423396B CN 202010363513 A CN202010363513 A CN 202010363513A CN 111423396 B CN111423396 B CN 111423396B
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dimethyladamantan
organic solvent
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陈国良
杜芳瑜
刘中博
周启璠
孙文娇
傅扬
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Shenyang Pharmaceutical University
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Abstract

The invention provides an sEH inhibitor, a preparation method and an application thereof, and relates to the technical field of endogenous active substance regulation. The sEH inhibitor in the sEH inhibitor provided by the invention has a structure shown in a formula I, R 1 And R 2 Independently include hydrogen, hydroxy, amino, mercapto, cyano, halogen, alkoxy, aromatic alkoxy, saturated hydrocarbon or heterocyclic group; x is an alkylene group; m comprises O or S;y comprises O, S, N, methylene, arylene, heterocyclylene, or heteroarylene; l comprises alkylene, arylene, heterocyclylene, or heteroarylene; r is 3 Including aliphatic amine groups, alcoholamine groups, aniline groups, naphthylamine groups, heterocyclic groups, heteroaryl groups, alkyl groups, cycloalkyl groups, halogens, hydroxyl groups, arylene groups, heterocyclylene groups, or heteroarylene groups. The compound provided by the invention has high inhibitory activity on human-derived HsEH and murine MsEH and small side effect, and can be used for preparing sEH inhibitors.

Description

sEH inhibitor, and preparation method and application thereof
Technical Field
The invention relates to the technical field of endogenous active substance regulation and control, and particularly relates to a sEH inhibitor, and a preparation method and application thereof.
Background
The cytokine storm refers to the phenomenon that a plurality of cytokines such as TNF-alpha, IL-1, IL-6, IL-12, IFN-alpha, IFN-beta, IFN-gamma, MCP-1, IL-8 and the like in body fluid are rapidly and massively generated after organisms are infected with microorganisms, and is an important reason for causing acute respiratory distress syndrome and multi-organ failure. Infection with coronavirus (COVID-2019) a small number of infected patients develop an inflammatory cytokine storm that leads to pneumonia, which can progress to different forms of respiratory distress, multiple organ failure and death. Even in survivors, fibropulmonary disease is common, and inflammation of the lungs of these patients is triggered by a series of uncontrolled chemical mediators, known as cytokine storms. In addition to supportive care, there are several pharmacological approaches to control this disease, one to block individual inflammatory cytokines, and another to use anti-inflammatory drugs. Approaches to blocking individual inflammatory cytokines are limited because specific cytokine receptor blockers reduce one cytokine, such as the IL-6 receptor antagonist tollizumab, and the like, while in reality cytokine storms are multiple or collective severe inflammatory cytokine storms such as TNF- α, IL-6, IL-1 β, IL-1, IL-8, G-CSF, MCP-1, IP-10, and MIP-1 α, and single cytokine receptor antagonists are insufficient to combat such cytokine storms, whereas conventional anti-inflammatory drugs, such as corticosteroids or non-steroidal anti-inflammatory drugs (e.g., ibuprofen), have immunosuppressive effects that may slow the body's clearance of pathogens such as viruses, and aggravate COVID-19 induced diseases (Lancet, 2020,395,473-475, and Lancet, 395, 683-684).
It has been found that epoxyeicosatrienoic acids (EETs) are capable of modulating pathways upstream of the endoplasmic reticulum stress pathway and converting them from a broad activator of inflammatory chemical mediators and cell death systems to an homeostatic system that maintains the balance of mediators and metabolites, through the endoplasmic reticulum stress pathway, maintaining resolution of inflammation and initiating repair mechanisms. In contrast, the conventional anti-inflammatory drugs act on the same principle as a switch, inflammation is either on or off, and cytochrome P450 enzymes produce epoxyeicosatrienoic acids (EETs) from arachidonic acid through the Endoplasmic Reticulum (ER) stress pathway to inhibit the production of inflammatory factors and cytokines, to progress the endoplasmic reticulum stress toward maintaining the inflammatory response balance in vivo, and to remodel the body inflammatory/anti-inflammatory balance to resolve inflammation and restore the patient to a normal and healthy biological state.
Further research shows that the EETs has a series of biological activities such as anti-inflammation, analgesia, anti-apoptosis, anti-fibrosis and anti-ischemia (Annu. Rev. Pharmacol. Toxicol.,2013, 53. For example, the study of Naqian (university of Huazhong Master 2013) found that exogenous EETs can inhibit the increase of the secretion of inflammatory factors IL-6, TNF-a and MCP-1 caused by 3T3-L1 fat cells and RAW264.7 macrophages by means of Toll-NF-kappa B signaling pathway to induce 3T3-L1 fat cells and RAW264.7 macrophages, and generate strong anti-inflammatory effect. Periwary (doctor thesis at southern and Central university 2013) reported that a soluble epoxide hydrolase (sEH) inhibitor TPPU inhibits the activation of inflamed bodies by increasing the amount of EETs in vivo, reduces LPS-induced inflammatory cell infiltration, edema, alveolar septal thickening and alveolar collapse in mice ALI lungs, inhibits the differentiation maturation of fibroblasts in lungs and EMT of alveolar epithelial cells to relieve pulmonary fibrosis secondary to ALI, promotes the proliferation of human bronchial epithelial cells, inhibits LPS-induced apoptosis, promotes the repair of injury of airway epithelia, and thus has a remarkable protective effect on acute lung injury/acute respiratory distress syndrome (ALI/ARDS). The fact that AA has a kidney protection effect through P450 metabolites EETs can play a role in relaxing blood vessels, reducing blood pressure, resisting apoptosis, resisting inflammation and the like is found by the qin and the like (physiology report, 2018,70 (6): 591-599.). Fermin and the like (Chinese and Western medicine combined nephropathy journal, 2013,14 (7): 641-644) find that EETs have biological action mechanisms of vasodilatation, inflammatory reaction regulation, fibrosis resistance and the like and protection effects on the aspects of preventing and treating renal diseases such as diabetic nephropathy, hypertensive nephropathy, acute renal injury, chronic renal failure and the like, and the EETs are considered to possibly provide new breakthrough for the intervention and treatment of various renal diseases, thereby having wide prospect and value. Yan xylol, etc. (China cardiovascular journal, 2015,20 (2): 151-154.) find that AA has the effect on heart failure through EETs which are metabolites of P450, and the EETs are considered to influence the occurrence and the development of the heart failure by influencing the pathophysiological processes of myocardial ischemia reperfusion injury, inflammatory reaction, myocardial apoptosis, myocardial hypertrophy, etc., and sEH becomes a new specific target point of the heart failure. Wu et al (Biochem Biophys Res Commun.2020, pii: S0006-291X (20) 30154-6.) reported that EETs can reduce blood brain barrier damage in diabetic mice and protect the brain and improve cognitive ability through activation of the AMPK/HO-1 pathway.
EETs are highly susceptible to metabolic inactivation by soluble epoxide hydrolase (sEH) in vivo, and DHETs, a dihydroxy metabolite of EETs, have an inflammatory effect, so that inhibition of sEH activity and increase of EETs in vivo become a novel method for treating diseases related to EETs. In the aspect of analgesics, the existing analgesics mainly comprise opioid analgesics, non-steroidal anti-inflammatory drugs and the like, and have large side effects, for example, the traditional opioid analgesics have strong effects, but also have strong addiction and side effects such as respiratory depression, blood pressure reduction, nausea, vomiting, constipation, dysuria and the like; the non-steroidal anti-inflammatory drugs can be divided into non-selective non-steroidal anti-inflammatory drugs and selective cyclooxygenase-2 (COX-2) inhibitors, and although the non-steroidal anti-inflammatory drugs also have a good analgesic effect, the non-selective non-steroidal anti-inflammatory drugs have severe gastrointestinal irritation and are easy to cause gastric ulcer, adverse reactions often exist on blood coagulation and hematopoietic systems, and the selective COX-2 inhibitors have no adverse reactions of gastrointestinal irritation but are easy to cause imbalance of prostacyclin and thromboxane, so that cardiovascular diseases are caused.
Disclosure of Invention
In view of the above, the present invention aims to provide a sEH inhibitor, a preparation method and an application thereof, and the sEH inhibitor provided by the present invention has high inhibitory activity on human soluble epoxy hydrolase (HsEH) and murine soluble epoxy hydrolase (MsEH), and has few side effects.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a sEH inhibitor having a structure shown in formula I, including isomer I-A and isomer I-B:
Figure BDA0002475795990000021
wherein R is 1 And R 2 Independently include hydrogen, hydroxy, amino, mercapto, cyano, halogen, alkoxy, aromatic alkoxy, saturated hydrocarbon or heterocyclic group;
x is an alkylene group, and n is an integer of 0 to 5;
m comprises O or S;
y comprises O, S, N, methylene, arylene, heterocyclylene, or heteroarylene;
l comprises alkylene, arylene, heterocyclylene, or heteroarylene;
c substituted as described for Y and L 6 ～C 10 The substituents in the aromatic group are independently C 1 ～C 6 Alkyl, cyano or halogen;
R 3 including aliphatic amine groups, alcohol amine groups, aniline groups, naphthylamine groups, heterocyclic groups, heteroaryl groups, alkyl groups, cycloalkyl groups, halogens, hydroxyl groups, arylene groups, heterocyclic groups or heteroarylene groups.
Preferably, in Y and L, the aromatic group independently comprises unsubstituted or substituted C 6 ～C 10 An aromatic group; said substituted C 6 ～C 10 The substituents in the aromatic group independently include C 1 ～C 6 Alkyl, cyano or halogen;
the heterocyclic group independently includes an unsubstituted or substituted 5-to 10-membered heterocyclic group;
the heteroaryl group independently includes an unsubstituted or substituted 5-to 10-membered heteroaryl group;
the heteroatoms in the heterocyclyl and heteroaryl groups independently comprise N, O, or S;
the substituents in said substituted 5-to 10-membered heterocyclyl and substituted 5-to 10-membered heteroaryl independently include-OR, -SR, -N (R) 2 、-C(O)R、-CO 2 R、-C(O)C(O)R、-C(O)CH 2 C(O)R、-S(O)R、-S(O) 2 R、-C(O)N(R) 2 、-SO 2 N(R) 2 -OC (O) R, -N (R) C (O) R or-N (R) 2 Wherein R includes C 1 ～C 6 An alkyl group.
Preferably, the alkylene group in L includes a C1-C6 saturated alkylene group or a C1-C6 unsaturated alkylene group.
Preferably, said R is 1 And R 2 Independently include hydrogen, methoxy, ethoxy, propoxy, isopropoxy, butoxy, cyclopentyloxy, cyclohexyloxy, phenoxy, benzyloxy, methyl, ethyl, propyl, butyl, pentyl, isobutyl, isopropyl, isopentyl, tert-butyl, hydroxy, amino, mercapto, cyano, or halogen; the halogen includes fluorine, chlorine or bromine.
Preferably, R 3 Wherein the fatty amine group is unsubstituted or substituted C 1 ～C 6 A fatty amine group;
the anilino group is unsubstituted or substituted anilino;
the naphthylamine group is unsubstituted or substituted naphthylamine group;
the heterocyclic group is an unsubstituted or substituted 5-to 10-membered heterocyclic group;
the heteroaryl is unsubstituted or substituted 5-to 10-membered heteroaryl;
the aryl is unsubstituted or substituted C 6 ～C 10 An aromatic group;
the heteroatoms in the heterocyclyl and heteroaryl groups independently comprise N, O, or S;
said substituted C 1 ～C 6 Fatty amino, substitutedAnilino group, substituted naphthylamino group, substituted 5-to 10-membered heterocyclic group, substituted 5-to 10-membered heteroaryl group and substituted C 6 ～C 10 The substituents in the aromatic group independently include-OR, -SR, -N (R) 2 、-C(O)R、-CO 2 R、-C(O)C(O)R、-C(O)CH 2 C(O)R、-S(O)R、-S(O) 2 R、-C(O)N(R) 2 、-SO 2 N(R) 2 -OC (O) R, -N (R) C (O) R or-N (R) 2 Wherein R is C 1 ～C 6 Alkyl or hydroxy.
Preferably, said R 3 Including halogen, hydroxy, methylamino, dimethylamino, ethylamino, 2-hydroxypropylamino, diethylamino, diethanolamino, phenethylamino, tetrahydropyrrolyl, piperidinyl, cyclohexylamino, morpholinyl, piperazinyl, N-methylpiperazinyl, N-ethylpiperazinyl, N-hydroxyethylpiperazinyl, phenyl, naphthyl, pyridcyclyl, thiophencyclyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl, pyrrolyl, pyrazolylcyclyl, benzimidazolyl, benzopyrrolyl, or benzopyrazolylcyclyl.
Preferably, the sEH inhibitors include N- (((1r, 3r,5s, 7r) -3, 5-dimethyladamantan-1-yl) -4-oxo-4- (piperidin-1-yl) butanamide, N 1 -cyclohexyl-N 4 - ((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) succinimide, N 1 - (((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) -N 4 -isobutylsuccinimide, (Z) -N- (((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) -4-oxo-4- (piperidin-1-yl) but-2-enamide, N 1 -cyclohexyl-N 4 - ((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) fumaramide, N 1 - ((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) -N 4 Isobutyl fumaroyl, N- (((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) -5-oxo-5- (piperidin-1-yl) pentanamide, N 1 -cyclohexyl-N 5 - (((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) glutaramide, N 1 - ((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) -N 5 Isobutylglutaramide, N- (((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) -4- (piperidine-1-carbonyl) benzamide, N 1 -cyclohexyl-N 4 -((1r,3R,5S7 r) -3, 5-dimethyladamantan-1-yl) terephthalamide, N 1 - ((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) -N 4 -isobutylterephthalamide, 1- ((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) -3- (4- (piperidine-1-carbonyl) phenyl) urea, N-cyclohexyl-4- (3- (((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) ureido) benzamide, 4- (3- ((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) ureido) -N-isobutylbenzamide, N 1 - (1- (((3r, 5r, 7r) -adamantan-1-yl) ethyl) -N 4 -isobutylsuccinimide, N 1 - (1- ((3r, 5r, 7r) -adamantan-1-yl) ethyl) -N 5 Isobutylglutaramide, 1- (1- (((1s, 3s) -adamantan-1-yl) ethyl) -3- (4- (piperidine-1-carbonyl) phenyl) urea, 4- (3- (1- (((1s, 3s) -adamantan-1-yl) ethyl) ureido) -N-cyclohexylbenzamide, 4- (3- (1- (((1s, 3s) -adamantan-1-yl) ethyl) ureido) -N-isobutylbenzamide, N 1 - (((1S, 2R, 5R) -adamantan-2-yl) -N 5 -isobutylglutaramide, 1- ((1S, 2R, 5R) -adamantan-2-yl) -3- (4- (piperidine-1-carbonyl) phenyl) urea, 4- (3- (((1S, 2R, 5R) -adamantan-2-yl) ureido) -N-cyclohexylbenzamide, 4- (3- (((1S, 2R, 5R) -adamantan-2-yl) ureido) -N-isobutylbenzamide, N 1 - ((5s, 7s) -5-hydroxyadamantan-2-yl) -N 5 Isobutylglutaramide, 1- ((5s, 7s) -5-hydroxyadamantan-2-yl) -3- (4- (piperidine-1-carbonyl) phenyl) urea, N-cyclohexyl-4- (3- (((5s, 7s) -5-hydroxyadamantan-2-yl) ureido) benzamide, 4- (3- ((5s, 7s) -5-hydroxyadamantan-2-yl) ureido) -N-isobutylbenzamide, 1- (((1r, 3s,5R, 7S) -3-hydroxyadamantan-1-yl) -3- (4- (piperidine-1-carbonyl) phenyl) urea, N-cyclohexyl-4- (3- (((1r, 3s,5R, 7S) -3-hydroxyadamantan-1-yl) ureido) benzamide or 4- (3- ((r, 1s, 5R, 7S) -3-hydroxyadamantan-1-yl) ureido) -N-isobutylbenzamide.
The invention provides a preparation method of the sEH inhibitor in the technical scheme, (1) when Y is methylene, the preparation method of the sEH inhibitor comprises the following steps:
mixing the compound a, the compound II and a first organic solvent, and carrying out a first acylation reaction to obtain a compound b;
mixing the compound b, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 1-hydroxybenzotriazole, a compound III, an organic base and a second organic solvent, and carrying out a second acylation reaction under an anhydrous condition to obtain the sEH inhibitor with the structure shown in the formula I;
the structural formulas of the compound a and the compound b are as follows:
Figure BDA0002475795990000041
(2) A method of making the sEH inhibitor when Y is an arylene, heterocyclylene, or heteroarylene, comprising the steps of:
mixing the compound c, thionyl chloride and a catalyst, and carrying out substitution reaction to obtain a compound d;
mixing the compound d, the compound III, the organic base, the 4-dimethylaminopyridine and a third organic solvent, and carrying out a third acylation reaction under an anhydrous condition to obtain a compound e;
mixing the compound e, a fourth organic solvent, water and inorganic base, adjusting the pH value to 1-4, and performing hydrolysis reaction to obtain a compound f;
mixing the compound f, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 1-hydroxybenzotriazole, organic base, a compound II and a fifth organic solvent, and carrying out fourth acylation reaction to obtain the sEH inhibitor with the structure shown in the formula I;
the structural formulas of the compound c, the compound d, the compound e and the compound f are as follows:
Figure BDA0002475795990000051
(3) A process for preparing the sEH inhibitor when Y is O, S or N, comprising the steps of:
mixing the compound II, organic base, compound g and a sixth organic solvent, and carrying out a fifth acylation reaction under an anhydrous condition to obtain a compound h;
mixing the compound h, palladium carbon and a seventh organic solvent in a hydrogen atmosphere, and carrying out a reduction reaction under an anhydrous condition to obtain a compound j;
mixing the compound j, phenyl chloroformate, an alkaline reagent and an eighth organic solvent, and carrying out sixth acylation reaction under an anhydrous condition to obtain a compound k;
mixing the compound k, the compound III, the organic base and a ninth organic solvent, and carrying out aminolysis reaction under anhydrous condition to obtain an sEH inhibitor with a structure shown in formula I;
the structural formulas of the compound g, the compound h, the compound j and the compound k are as follows:
Figure BDA0002475795990000052
the structural formula of the compound II in the (1), (2) and (3) is R 3 H；
The structural formula of the compound III in (1), (2) and (3) is as follows:
Figure BDA0002475795990000053
preferably, the first, third, sixth, and eighth organic solvents independently comprise dichloromethane, chloroform, 1, 2-dichloroethane, ethyl acetate, tetrahydrofuran, acetonitrile, dioxane, or acetone;
the second organic solvent comprises dichloromethane, chloroform, 1, 2-dichloroethane, N-dimethylformamide or tetrahydrofuran;
the catalyst comprises N, N-dimethylformamide, pyridine, triethylamine or 4-dimethylaminopyridine;
the fourth and ninth organic solvents independently comprise tetrahydrofuran, dioxane, or acetonitrile;
the fifth organic solvent comprises chloroform, 1, 2-dichloroethane, N-dimethylformamide, or tetrahydrofuran;
the seventh organic solvent comprises absolute ethyl alcohol, absolute methyl alcohol, isopropanol, dichloromethane, tetrahydrofuran or n-hexane.
The invention also provides application of the sEH inhibitor in the technical scheme or the sEH inhibitor prepared by the preparation method in the technical scheme in preparing a medicament for treating soluble epoxide hydrolase mediated diseases.
The sEH inhibitor with the structure shown in the formula I has a classical pharmacodynamic combination mode of the sEH, such as a hydrophobic segment, a core urea structure, an amide structure and a terminal polar segment, and a memantine segment is introduced at the hydrophobic segment to adjust the hydrophobic property of the compound. In addition, the appropriate distance between the carbonyl group of the urea and the amide carbonyl group greatly increases the binding capacity with the sEH, so that the inhibitory activity on human-derived HsEH and murine MsEH is high, and the compound can be used for preparing sEH inhibitors.
The preparation method provided by the invention is simple to operate, high in yield and suitable for industrial production.
Detailed Description
The invention provides a sEH inhibitor having a structure shown in formula I, including isomer I-A and isomer I-B:
Figure BDA0002475795990000061
wherein R is 1 And R 2 Independently include hydrogen, hydroxy, amino, mercapto, cyano, halogen, C 1 ～C 6 Alkoxy radical, C 1 ～C 6 A saturated hydrocarbon group or a heterocyclic group;
x is an alkylene group, and n is an integer of 0 to 5;
m comprises O or S;
y comprises O, S, N, methylene, arylene, heterocyclylene, or heteroarylene;
l comprises alkylene, arylene, heterocyclylene, or heteroarylene;
R 3 including fatty amine group, alcamine group, aniline group, naphthylamine group, heterocyclic group, heteroaryl group, alkyl group, cycloalkyl group, halogen and hydroxyl groupA group, an arylene group, a heterocyclylene group, or a heteroarylene group.
In the present invention, R 1 And R 2 Independently comprises hydrogen, hydroxyl, amino, sulfydryl, cyano, halogen, alkoxy, aromatic alkoxy, saturated alkyl or heterocyclic radical, and the alkoxy is preferably C 1 ～C 6 Alkoxy, the saturated hydrocarbon radical is preferably C 1 ～C 6 A saturated hydrocarbon group, the heterocyclic group preferably being a 5-to 10-membered heterocyclic group, more preferably independently including hydrogen, methoxy, ethoxy, propoxy, isopropoxy, butoxy, cyclopentyloxy, cyclohexyloxy, phenoxy, benzyloxy, methyl, ethyl, propyl, butyl, pentyl, isobutyl, isopropyl, isopentyl, tert-butyl, hydroxy, amino, mercapto, cyano or halogen; the halogen preferably comprises fluorine, chlorine or bromine. In the present invention, the hetero atom in the heterocyclic group preferably includes N, O or S.
In the present invention, when R is 1 When it is methyl, R 2 Preferably methyl; when R is 1 When it is methyl, R 2 Preferably methyl; when R is 1 When it is hydroxy, R 2 Preferably hydrogen; when R is 1 When it is hydrogen, R 2 Preferably hydrogen; when R is 1 When it is hydrogen, R 2 Hydroxyl groups are preferred.
In the present invention, X is an alkylene group, preferably a saturated alkylene group, more preferably a linear saturated alkylene group or a branched saturated alkylene group, and still more preferably a methylene group, an ethylene group, a propylene group, a butylene group, an isopropylene-butyl group, a 2-methylbutylene group, a 2, 2-dimethylbutylene group, a 2-isopropylene group, a 2-methylpropylene group or a 2-isopropylene group. In the present invention, n is an integer of 0 to 5, preferably 0 or 1.
In the present invention, in Y and L, the aromatic group preferably includes unsubstituted or substituted C 6 ～C 10 Aryl, said substituted C 6 ～C 10 The substituents in the aromatic group independently include C 1 ～C 6 Alkyl, cyano or halogen, preferably including fluorine, chlorine or bromine. In the present invention, in Y and L, the heterocyclic group preferably includes unsubstituted or substitutedA 5-to 10-membered heterocyclic group, and the heteroaryl group preferably includes an unsubstituted or substituted 5-to 10-membered heteroaryl group; the substituents in said substituted 5-to 10-membered heterocyclyl and substituted 5-to 10-membered heteroaryl independently include-OR, -SR, -N (R) 2 、-C(O)R、-CO 2 R、-C(O)C(O)R、-C(O)CH 2 C(O)R、-S(O)R、-S(O) 2 R、-C(O)N(R) 2 、-SO 2 N(R) 2 -OC (O) R, -N (R) C (O) R or-N (R) 2 Wherein R includes C 1 ～C 6 An alkyl group. In the present invention, the hetero atom in the heterocyclic group preferably includes N, O or S. In the present invention, the alkylene group in L is preferably C 1 ～C 6 Saturated alkylene or C 1 ～C 6 Unsaturated alkylene groups, more preferably methylene, ethylene, propylene, butylene, pentylene, hexylene, cyclohexylene.
In the present invention, R 3 Including aliphatic amine, alcohol amine, aniline, naphthylamine, heterocyclic radical, heteroaryl, alkyl, naphthenic radical, halogen, hydroxyl, arylene radical, heterocyclic radical or heteroarylene radical; the fatty amine group is preferably unsubstituted or substituted C 1 ～C 6 A fatty amine group; the alkanolamine group is preferably an unsubstituted or substituted alkanolamine group; the anilino group is preferably an unsubstituted or substituted anilino group; the naphthylamine group is preferably an unsubstituted or substituted naphthylamine group; the heterocyclic group is preferably an unsubstituted or substituted 5-to 10-membered heterocyclic group; the heteroaryl group is preferably an unsubstituted or substituted 5-to 10-membered heteroaryl group; the aromatic group is preferably unsubstituted or substituted C 6 ～C 10 An aromatic group. In the present invention, the heteroatoms in the heterocyclic group and the heteroaryl group independently include N, O or S. In the present invention, said substituted C 1 ～C 6 Aliphatic amine group, substituted alcohol amine group, substituted aniline group, substituted naphthylamine group, substituted 5-10 membered heterocyclic group, substituted 5-10 membered heteroaryl group and substituted C 6 ～C 10 The substituents in the aromatic group independently include-OR, -SR, -N (R) 2 、-C(O)R、-CO 2 R、-C(O)C(O)R、-C(O)CH 2 C(O)R、-S(O)R、-S(O) 2 R、-C(O)N(R) 2 、-SO 2 N(R) 2 -OC (O) R, -N (R) C (O) R or-N (R) 2 Wherein R is C 1 ～C 6 Alkyl or hydroxyl.
In the present invention, said R 3 Further preferably includes halogen, hydroxy, methylamino, dimethylamino, ethylamino, 2-hydroxypropylamino, diethylamino, diethanolamino, phenethylamino, tetrahydropyrrolyl, piperidinyl, cyclohexylamino, morpholinyl, piperazinyl, N-methylpiperazinyl, N-ethylpiperazinyl, N-hydroxyethylpiperazinyl, phenyl, naphthyl, pyridcyclyl, thiophencyclyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl, pyrrolyl, pyrazolinyl, benzimidazolyl, benzopyrrolyl or benzopyrazolyl. In the present invention, the phenyl group, naphthyl group, pyridine group, thiophene group, pyrimidine group, indole group, quinoline group, isoquinoline group, pyrrole group, pyrazole group, benzimidazolyl group, benzopyrrole group and benzopyrrole group independently contain a substituent or do not contain a substituent, and the substituent independently includes C 1 ～C 6 Alkyl or hydroxy.
In the present invention, the sEH inhibitor preferably includes N- (((1r, 3r,5s, 7r) -3, 5-dimethyladamantan-1-yl) -4-oxo-4- (piperidin-1-yl) butanamide, N 1 -cyclohexyl-N 4 - ((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) succinimide, N 1 - (((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) -N 4 -isobutylsuccinimide, (Z) -N- (((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) -4-oxo-4- (piperidin-1-yl) but-2-enamide, N 1 -cyclohexyl-N 4 - ((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) fumaramide, N 1 - ((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) -N 4 Isobutyl fumaroyl, N- (((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) -5-oxo-5- (piperidin-1-yl) pentanamide, N 1 -cyclohexyl-N 5 - (((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) glutaramide, N 1 - ((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) -N 5 Isobutylglutaramide, N- (((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) -4- (piperidine-1-carbonyl) benzamide, N 1 -cyclohexyl-N 4 - ((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) terephthalamide, N 1 - ((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) -N 4 Isobutylterephthalamide, 1- ((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) -3- (4- (piperidine-1-carbonyl) phenyl) urea, N-cyclohexyl-4- (3- (((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) ureido) benzamide, 4- (3- ((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) ureido) -N-isobutylbenzamide, N 1 - (1- (((3r, 5r, 7r) -adamantan-1-yl) ethyl) -N 4 -isobutyl succinimide, N 1 - (1- ((3r, 5r, 7r) -adamantan-1-yl) ethyl) -N 5 Isobutyl glutaramide, 1- (1- (((1s, 3s) -adamantan-1-yl) ethyl) -3- (4- (piperidine-1-carbonyl) phenyl) urea, 4- (3- (1- (((1s, 3s) -adamantan-1-yl) ethyl) ureido) -N-cyclohexylbenzamide, 4- (3- (1- (((1s, 3s) -adamantan-1-yl) ethyl) ureido) -N-isobutylbenzamide, N 1 - (((1S, 2R, 5R) -adamantan-2-yl) -N 5 -isobutylglutaramide, 1- ((1S, 2R, 5R) -adamantan-2-yl) -3- (4- (piperidine-1-carbonyl) phenyl) urea, 4- (3- (((1S, 2R, 5R) -adamantan-2-yl) ureido) -N-cyclohexylbenzamide, 4- (3- (((1S, 2R, 5R) -adamantan-2-yl) ureido) -N-isobutylbenzamide, N 1 - ((5s, 7s) -5-hydroxyadamantan-2-yl) -N 5 Isobutyl glutaramide, 1- ((5s, 7s) -5-hydroxyadamantan-2-yl) -3- (4- (piperidine-1-carbonyl) phenyl) urea, N-cyclohexyl-4- (3- (((5s, 7s) -5-hydroxyadamantan-2-yl) ureido) benzamide, 4- (3- ((5s, 7s) -5-hydroxyadamantan-2-yl) ureido) -N-isobutylbenzamide, 1- (((1r, 3s,5r, 7s) -3-hydroxyadamantan-1-yl) -3- (4- (piperidine-1-carbonyl) phenyl) urea, N-cyclohexyl-4- (3- (((1r, 3s,5r, 7s) -3-hydroxyadamantan-1-yl) ureido) benzamide or 4- (3- ((r, 3s,5r, 7s) -3-hydroxyadamantan-1-yl) ureido) -N-isobutylbenzamide, the structural formula of the sEH inhibitor described above preferably being represented by formulae I-1 to 31:
Figure BDA0002475795990000081
Figure BDA0002475795990000091
the invention provides a preparation method of the sEH inhibitor in the technical scheme, (1) when Y is methylene, the preparation method of the sEH inhibitor comprises the following steps:
mixing the compound a, the compound II and a first organic solvent, and carrying out a first acylation reaction to obtain a compound b;
mixing the compound b, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 1-hydroxybenzotriazole, a compound III, an organic base and a second organic solvent, and carrying out a second acylation reaction under an anhydrous condition to obtain the sEH inhibitor with the structure shown in the formula I;
the structural formulas of the compound a and the compound b are as follows:
Figure BDA0002475795990000092
(2) A method of making the sEH inhibitor when Y is an arylene, heterocyclylene, or heteroarylene, comprising the steps of:
mixing the compound c, thionyl chloride and a catalyst, and carrying out substitution reaction to obtain a compound d;
mixing the compound d, the compound III, organic base, 4-dimethylaminopyridine and a third organic solvent, and carrying out a third acylation reaction under an anhydrous condition to obtain a compound e;
mixing the compound e, a fourth organic solvent, water and inorganic base, adjusting the pH value to 1-4, and performing hydrolysis reaction to obtain a compound f;
mixing the compound f, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 1-hydroxybenzotriazole, organic base, a compound II and a fifth organic solvent, and carrying out fourth acylation reaction to obtain the sEH inhibitor with the structure shown in the formula I;
the structural formulas of the compound c, the compound d, the compound e and the compound f are as follows:
Figure BDA0002475795990000093
(3) A process for preparing the sEH inhibitor when Y is O, S or N, comprising the steps of:
mixing the compound II, organic base, the compound g and a sixth organic solvent, and carrying out a fifth acylation reaction under an anhydrous condition to obtain a compound h;
mixing the compound h, palladium carbon and a seventh organic solvent in a hydrogen atmosphere, and carrying out a reduction reaction under an anhydrous condition to obtain a compound j;
mixing the compound j, phenyl chloroformate, an alkaline reagent and an eighth organic solvent, and carrying out sixth acylation reaction under an anhydrous condition to obtain a compound k;
mixing the compound k, the compound III, the organic base and a ninth organic solvent, and carrying out aminolysis reaction under anhydrous condition to obtain an sEH inhibitor with a structure shown in formula I;
the structural formulas of the compound g, the compound h, the compound j and the compound k are as follows:
Figure BDA0002475795990000101
the structural formula of the compound II in the (1), (2) and (3) is R 3 H；
The structural formula of the compound III in (1), (2) and (3) is as follows:
Figure BDA0002475795990000102
in the present invention, all the raw material components are commercially available products well known to those skilled in the art unless otherwise specified.
When Y is methylene, a process for preparing the sEH inhibitor comprising the steps of:
mixing the compound a, the compound II and a first organic solvent, and carrying out a first acylation reaction to obtain a compound b;
mixing the compound b, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 1-hydroxybenzotriazole, a compound III, an organic base and a second organic solvent, and carrying out a second acylation reaction under an anhydrous condition to obtain the sEH inhibitor with the structure shown in the formula I;
the structural formulas of the compound a and the compound b are as follows: compound a compound b.
The reaction route is shown as formula (1):
Figure BDA0002475795990000103
the compound a, the compound II and a first organic solvent are mixed for a first acylation reaction to obtain a compound b.
In the present invention, in the formula (1), M, L, R 1 、R 2 、R 3 And the optional groups of X are respectively the same as M, L and R in the technical scheme 1 、R 2 、R 3 The range of n is preferably the same as that of n in the above technical scheme, and is not described in detail herein; and Y is methylene.
In the present invention, the compound a is preferably an acid anhydride; in embodiments of the present invention, the compound a preferably comprises succinic anhydride, glutaric anhydride or maleic anhydride. In the present invention, the molar ratio of the compound a to the compound II is preferably 1: (0.8 to 3), more preferably 1: (1-2), most preferably 1.
In the invention, the structural formula of the compound II is R 3 H, wherein R 3 And R in the above technical scheme 3 The optional substituent groups are the same and are not described in detail here. In an embodiment of the present invention, the compound II preferably comprises piperidine, cyclohexylamine or isobutylamine.
In the present invention, the first organic solvent preferably includes dichloromethane, chloroform, 1, 2-dichloroethane, ethyl acetate, tetrahydrofuran, acetonitrile, dioxane, or acetone. In the present invention, the ratio of the mass of the compound a to the volume of the first organic solvent is preferably 1g: (2-10) mL, more preferably 1g: (4-6) mL.
In the present invention, the mixing method is preferably stirring mixing, and the speed and time of stirring mixing are not particularly limited in the present invention, and the raw materials may be uniformly mixed. In the present invention, the mixing order is preferably that the compound a is dissolved in the first organic solvent, and the compound II is added dropwise to the resulting compound a solution under ice bath conditions. The dropping speed is not particularly limited in the invention, and the dropping can be carried out dropwise. In the present invention, the temperature of the ice bath condition is preferably 0 to 5 ℃.
In the present invention, the temperature of the first acylation reaction is preferably 15 to 40 ℃, more preferably 18 to 30 ℃; in the present embodiment, the first acylation reaction is preferably performed at room temperature. In the present invention, the time for the first acylation reaction is preferably 2 to 10 hours, more preferably 3 to 5 hours.
After the first acylation reaction, the present invention preferably further comprises concentrating the system of the first acylation reaction, and recrystallizing the obtained concentrate to obtain compound b. The concentration method of the present invention is not particularly limited, and a concentration method known to those skilled in the art may be used, specifically, reduced pressure distillation, and the conditions of the reduced pressure distillation are not particularly limited, and distillation under reduced pressure is performed until no solvent flows out. In the present invention, the solvent for recrystallization preferably includes ethyl acetate, methanol, ethanol, acetone, or acetonitrile, and the mass ratio of the solvent for recrystallization to the concentrate is preferably (4 to 10): 1, more preferably (5 to 8): 1.
after the compound b is obtained, the compound b, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 1-hydroxybenzotriazole, a compound III, an organic base and a second organic solvent are mixed, and a second acylation reaction is carried out under the anhydrous condition to obtain the sEH inhibitor with the structure shown in the formula I.
In the present invention, the organic base preferably includes triethylamine, pyridine or N, N-diisopropylethylamine.
In the present invention, the structural formula of the compound III is as follows:
Figure BDA0002475795990000111
wherein R is 1 、R 2 Optional groups of X are preferably as defined above for R in the above-mentioned technical scheme 1 、R 2 The optional groups of X are the same and are not described in detail herein; the n is preferably an integer of 1 to 5, more preferably 0 or 1.
In the present invention, the compound III preferably includes memantine hydrochloride, memantine, rimantadine hydrochloride, rimantadine, 2-amantadine, trans-4-amino-1-adamantanol or 3-amino-1-adamantanol.
In the present invention, the molar ratio of the compound b, 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDCI), 1-hydroxybenzotriazole (HOBt) and compound III is preferably 1: (1-3): (1-3): (1-2), more preferably 1: (1.5-2.5): (1.5-2.5): (1-1.5), most preferably 1:1.5:1.5:1. in the present invention, the EDCI and HOBt function as condensing agents.
In the present invention, the organic base preferably includes triethylamine, pyridine or N, N-diisopropylethylamine. In the present invention, the molar ratio of the compound b to the organic base is preferably 1:2 to 10, more preferably 1:3 to 8, most preferably 1.
In the present invention, the second organic solvent preferably includes dichloromethane, chloroform, 1, 2-dichloroethane, N-dimethylformamide, or tetrahydrofuran. In the present invention, the second organic solvent is preferably dried before use, and the drying method of the second organic solvent in the present invention is not particularly limited, and any drying method of an organic solvent known to those skilled in the art may be used. In the present invention, the ratio of the mass of the compound b to the volume of the second organic solvent is preferably 1g: (5-20) mL, more preferably 1g: (10-15) mL.
In the present invention, the mixing method is preferably stirring mixing, and the speed and time of the stirring mixing are not particularly limited in the present invention, and the raw materials may be uniformly mixed. In the present invention, the order of mixing is preferably to premix compound b, EDCI, HOBt, and the second organic solvent, and to add compound III to the resulting mixture. In the present invention, the time for the premixing is preferably 10 to 60min, more preferably 30 to 40min.
In the present invention, the temperature of the second acylation reaction is preferably 15 to 40 ℃, more preferably 18 to 30 ℃; in the present embodiment, the second acylation reaction is preferably carried out at room temperature. In the present invention, the time for the second acylation reaction is preferably 2 to 12 hours, and more preferably 4 to 8 hours.
After the second acylation reaction, the method preferably further comprises the steps of adding water into a product system of the second acylation reaction, extracting with an organic solvent, sequentially washing the obtained organic phase with a saturated sodium carbonate solution, washing with water, washing with a saturated salt solution, drying with anhydrous magnesium sulfate, carrying out solid-liquid separation, concentrating the obtained liquid-phase component, and recrystallizing the obtained concentrate to obtain the sEH inhibitor with the structure shown in the formula I. The addition amount of the water is not particularly limited, and the water can be separated from an organic phase by liquid-liquid separation. In the present invention, the organic solvent is preferably dichloromethane, and the amount of the organic solvent used in the present invention is not particularly limited, and may be any amount known to those skilled in the art. In the present invention, the number of times of washing with the saturated sodium carbonate solution is not particularly limited, and unreacted carboxylic acid may be removed. The number of times of the water washing is not particularly limited, and the pH value of the obtained water washing liquid is neutral. The solid-liquid separation mode is not particularly limited, and a solid-liquid separation mode known to those skilled in the art can be adopted, such as suction filtration. The concentration method of the present invention is not particularly limited, and a concentration method known to those skilled in the art may be used, specifically, reduced pressure distillation, and the conditions of the reduced pressure distillation are not particularly limited, and distillation under reduced pressure is performed until no solvent flows out. In the present invention, the solvent for recrystallization preferably includes acetone, methanol, ethanol, ethyl acetate, or acetonitrile, and the mass ratio of the solvent for recrystallization to the concentrate is preferably (2 to 10): 1, more preferably (4 to 8): 1.
a method of making the sEH inhibitor when Y is an arylene, heterocyclylene, or heteroarylene, comprising the steps of:
mixing the compound c, thionyl chloride and a catalyst, and carrying out substitution reaction to obtain a compound d;
mixing the compound d, the compound III, organic base, 4-dimethylaminopyridine and a third organic solvent, and carrying out a third acylation reaction under an anhydrous condition to obtain a compound e;
mixing the compound e, a fourth organic solvent, water and inorganic base, adjusting the pH value to 1-4, and performing hydrolysis reaction to obtain a compound f;
mixing the compound f, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 1-hydroxybenzotriazole, organic base, a compound II and a fifth organic solvent, and carrying out a fourth acylation reaction to obtain an sEH inhibitor with a structure shown in a formula I;
the structural formulas of the compound c, the compound d, the compound e and the compound f are as follows:
Figure BDA0002475795990000131
wherein Y is an aryl, heterocyclic or heteroaryl group; l alkyl, aryl, heterocyclic or heteroaryl.
The reaction route which takes place is shown in formula (2):
Figure BDA0002475795990000132
in the present invention, M, L, R in the formula (2) 1 、R 2 、R 3 And the optional groups of X are respectively the same as M, L and R in the technical scheme 1 、R 2 、R 3 And the optional groups X are the same, and the range of n is preferably the same as that of n in the technical scheme, and the description is omitted.
The compound c, thionyl chloride and a catalyst are mixed for substitution reaction to obtain a compound d.
In the present invention, the molar ratio of the compound c and thionyl chloride is preferably 1: (2 to 10), more preferably 1: (3 to 8), most preferably 1: (4-6).
In the present invention, the catalyst preferably comprises N, N-Dimethylformamide (DMF), pyridine, triethylamine or 4-dimethylaminopyridine. In the present invention, the ratio of the molar amount of the compound c to the volume of the catalyst is preferably 1mmol: (3-20) mL, more preferably 1mmol: (5-15) mL.
In the present invention, the mixing method is preferably stirring mixing, and the speed and time of stirring mixing are not particularly limited in the present invention, and the raw materials may be uniformly mixed.
In the present invention, the temperature of the substitution reaction is preferably 40 to 80 ℃, more preferably 60 to 80 ℃; the time for the substitution reaction is preferably 1 to 8 hours, more preferably 2 to 6 hours.
After the substitution reaction, the present invention preferably further comprises concentrating a product system of the substitution reaction and cooling to room temperature to obtain a compound d. The present invention is not particularly limited in the manner of concentration, and may employ a concentration method known to those skilled in the art, specifically, vacuum distillation, and the present invention is not particularly limited in the conditions of vacuum distillation, and may employ vacuum distillation until no solvent flows out. The cooling method of the present invention is not particularly limited, and a cooling method known to those skilled in the art may be used.
After the compound d is obtained, the compound d, the compound III, the organic base, the 4-dimethylaminopyridine and the third organic solvent are mixed, and a third acylation reaction is carried out under the anhydrous condition to obtain a compound e.
In the present invention, the organic base preferably includes triethylamine, pyridine or N, N-diisopropylethylamine. In the present invention, the molar ratio of the compound III, the compound d, the organic base and the 4-dimethylaminopyridine is preferably 1: (1-4): (2-10): (0.1 to 0.5), more preferably 1: (2-3): (3-8): (0.2 to 0.4), most preferably 1:2:5:0.2.
in the present invention, the third organic solvent preferably includes dichloromethane, chloroform, 1, 2-dichloroethane, ethyl acetate, tetrahydrofuran, acetonitrile, dioxane, or acetone. In the present invention, the third organic solvent is preferably dried before use, and the drying method of the third organic solvent in the present invention is not particularly limited, and any drying method of an organic solvent known to those skilled in the art may be used.
In the present invention, the mixing method is preferably stirring mixing, and the speed and time of stirring mixing are not particularly limited in the present invention, and the raw materials may be uniformly mixed. In the present invention, the mixing order is preferably to premix the compound III, the organic base, 4-Dimethylaminopyridine (DMAP) and a part of the third organic solvent to obtain a mixed solution; mixing the compound d with the residual third organic solvent to obtain a compound d solution; and (3) dropping the compound d solution after the temperature of the mixed solution is reduced to-15-10 ℃. In the present invention, the temperature of the mixed solution is further preferably lowered to 0 ℃. The dropping speed is not particularly limited in the invention, and the dropping can be carried out dropwise. In the present invention, the ratio of the molar amount of the compound III to the volume of a part of the third organic solvent is preferably 1mmol: (1-10) mL, more preferably 1mmol: (3-8) mL. In the present invention, the ratio of the mass molar amount of the compound d to the volume of the remaining third organic solvent is preferably 1mmol: (0.5 to 5) mL, more preferably 1mmol: (1-2) mL.
In the present invention, the temperature of the third acylation reaction is preferably 15 to 40 ℃, more preferably 18 to 30 ℃; in the embodiment of the present invention, the third acylation reaction is preferably performed under room temperature conditions. In the present invention, the time for the third acylation reaction is preferably 4 to 12 hours, and more preferably 6 to 8 hours.
After the third acylation reaction, the method preferably further comprises the steps of adding water into a system of the third acylation reaction, extracting with an organic solvent, sequentially washing the obtained organic phase with a saturated sodium carbonate solution, washing with water, washing with a saturated salt solution, drying with anhydrous magnesium sulfate, and carrying out solid-liquid separation, and concentrating the obtained liquid phase component to dryness to obtain the compound e. The addition amount of the water is not particularly limited, and the water can be separated from an organic phase in a liquid-liquid manner. In the present invention, the organic solvent used for the extraction is preferably dichloromethane, and the amount of the organic solvent used in the present invention is not particularly limited, and may be any amount known to those skilled in the art. The invention has no special limit on the washing times of the saturated sodium carbonate solution, and can remove a small amount of unreacted raw materials and hydrogen chloride generated in the reaction. The number of times of the water washing is not particularly limited, and the method can be implemented until no gas is generated in the solution. The solid-liquid separation mode is not particularly limited, and a solid-liquid separation mode known to those skilled in the art can be adopted, such as suction filtration. The concentration method of the present invention is not particularly limited, and a concentration method known to those skilled in the art may be used, specifically, reduced pressure distillation, and the conditions of the reduced pressure distillation are not particularly limited, and distillation under reduced pressure is performed until no solvent flows out.
After the compound e is obtained, the compound e, a fourth organic solvent, water and inorganic base are mixed, the pH value is adjusted to 1-4, and hydrolysis reaction is carried out to obtain a compound f.
In the present invention, the inorganic base preferably includes lithium hydroxide, sodium hydroxide, potassium hydroxide, or cesium carbonate. In the present invention, the molar ratio of the compound e to the inorganic base is preferably 1: (2 to 10), more preferably 1: (3 to 8), most preferably 1: (3-5).
In the present invention, the fourth organic solvent preferably includes Tetrahydrofuran (THF) dioxane or acetonitrile. In the present invention, the ratio of the molar amount of the compound e, the volume of the fourth organic solvent, and the volume of water is preferably 1mmol: (2-10) mL: (2-10) mL, more preferably 1mmol: (3-8) mL: (3-8) mL.
In the present invention, the mixing method is preferably stirring mixing, and the speed and time of the stirring mixing are not particularly limited in the present invention, and the raw materials may be uniformly mixed. In the present invention, the inorganic base is hydrolyzed during the mixing process.
After the mixing, the invention preferably further comprises solid-liquid separation of the mixed product system, concentration of the obtained liquid phase component to dryness, and addition of water to the obtained concentrate. The solid-liquid separation mode is not particularly limited, and a solid-liquid separation mode known to those skilled in the art can be adopted, such as suction filtration. The present invention is not particularly limited in the manner of concentration, and may employ a concentration method known to those skilled in the art, specifically, vacuum distillation, and the present invention is not particularly limited in the conditions of vacuum distillation, and may employ vacuum distillation until no solvent flows out. The amount of water added in the invention is not particularly limited, and water is added until the obtained reaction solution is clear.
In the present invention, the pH adjustment is preferably performed using a mineral acid, which preferably includes a hydrochloric acid solution; the concentration of the hydrochloric acid solution is not particularly limited, and the pH value can be adjusted to 1-4; in the embodiment of the invention, the concentration of the hydrochloric acid solution is preferably 1mol/L; the pH is more preferably 1 to 2. In the present invention, the pH adjustment is preferably performed under ice bath conditions.
In the present invention, the temperature of the hydrolysis reaction is preferably 15 to 40 ℃, more preferably 18 to 30 ℃; in the embodiment of the present invention, the hydrolysis reaction is preferably performed at room temperature. In the present invention, the time for the hydrolysis reaction is preferably 2 to 10 hours, and more preferably 3 to 5 hours. In the present invention, in the hydrolysis reaction process, the hydrolysis product of the inorganic base reacts with hydrogen ions to generate a carboxylic acid product.
After the hydrolysis reaction, the invention preferably performs solid-liquid separation on a product system of the hydrolysis reaction, and sequentially washes and dries the obtained solid component to obtain the compound f. The solid-liquid separation mode is not particularly limited, and a solid-liquid separation mode known to those skilled in the art can be adopted, such as suction filtration. In the present invention, the number of times of the washing with water is not particularly limited, and the obtained washing solution may have a pH of 4, and in this case, the residual inorganic acid can be surely washed. In the present invention, the drying temperature and time are not particularly limited, and the drying may be carried out to a constant weight.
After the compound f is obtained, the compound f, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 1-hydroxybenzotriazole, organic base, the compound II and a fifth organic solvent are mixed for a fourth acylation reaction to obtain the sEH inhibitor with the structure shown in the formula I.
In the present invention, the organic base preferably includes triethylamine, pyridine or N, N-diisopropylethylamine. In the present invention, the molar ratio of the compound f, 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDCI), 1-hydroxybenzotriazole (HOBt), organic base and compound II is preferably 1: (1-3): (1-3): (2-10): (1-2), more preferably 1: (1.5-2.5): (1.5-2.5): (4-8): (1.1 to 1.8), most preferably 1:1.5:1.5:5:1.2.
in the present invention, the fifth organic solvent preferably includes tetrahydrofuran, chloroform, 1, 2-dichloroethane or N, N-dimethylformamide. In the present invention, the fifth organic solvent is preferably dried before use, and the drying method of the fifth organic solvent is not particularly limited in the present invention, and any drying method of an organic solvent known to those skilled in the art may be used. In the present invention, the ratio of the molar amount of the compound f to the volume of the fifth organic solvent is preferably 1mmol: (5 to 25) mL, more preferably 1mmol: (10-20) mL.
In the present invention, the mixing method is preferably stirring mixing, and the speed and time of the stirring mixing are not particularly limited in the present invention, and the raw materials may be uniformly mixed. In the present invention, the order of mixing is preferably that compound f, EDCI, HOBt, the organic base, and the fifth organic solvent are premixed, and compound II is added to the resulting mixture. In the present invention, the time for the premixing is preferably 10 to 60min, more preferably 30 to 40min.
In the present invention, the temperature of the fourth acylation reaction is preferably 20 to 60 ℃, more preferably 40 to 50 ℃; the time of the fourth acylation reaction is preferably 8 to 24 hours, more preferably 10 to 15 hours, and most preferably 12 hours.
After the fourth acylation reaction, the invention preferably further comprises adding water into the system of the fourth acylation reaction, extracting with an organic solvent, sequentially washing the obtained organic phase with water, washing with saturated salt solution, drying with anhydrous magnesium sulfate, separating solid from liquid, concentrating the obtained liquid phase component, and recrystallizing the obtained concentrate to obtain the sEH inhibitor with the structure shown in formula I. The addition amount of the water is not particularly limited, and the water can be separated from an organic phase by liquid-liquid separation. In the present invention, the extractant used in the extraction is preferably dichloromethane, and the amount of the organic solvent used in the present invention is not particularly limited, and may be any amount known to those skilled in the art. The number of times of the water washing is not particularly limited, and the water washing is carried out until the pH value of the obtained water washing liquid is neutral. The solid-liquid separation mode is not particularly limited, and a solid-liquid separation mode known to those skilled in the art can be adopted, such as suction filtration. The present invention is not particularly limited in the manner of concentration, and may employ a concentration method known to those skilled in the art, specifically, vacuum distillation, and the present invention is not particularly limited in the conditions of vacuum distillation, and may employ vacuum distillation until no solvent flows out. In the present invention, the solvent for recrystallization preferably includes acetone, methanol, ethanol, acetonitrile, or ethyl acetate, and the mass ratio of the solvent for recrystallization to the concentrate is preferably (10 to 20): 1, more preferably (12 to 18): 1, most preferably 15.
When Y is O, S or N, the preparation method of the sEH inhibitor comprises the following steps:
mixing the compound II, organic base, compound g and a sixth organic solvent, and carrying out a fifth acylation reaction under an anhydrous condition to obtain a compound h;
mixing the compound h, palladium carbon and a seventh organic solvent in a hydrogen atmosphere, and carrying out a reduction reaction under an anhydrous condition to obtain a compound j;
mixing the compound j, phenyl chloroformate, an alkaline reagent and an eighth organic solvent, and carrying out sixth acylation reaction under an anhydrous condition to obtain a compound k;
mixing the compound k, the compound III, the organic base and a ninth organic solvent, and carrying out aminolysis reaction under anhydrous condition to obtain a sEH inhibitor with a structure shown in formula I;
the structural formulas of the compound g, the compound h, the compound j and the compound k are as follows:
Figure BDA0002475795990000161
wherein Y is O, S or N, L comprises alkyl, aryl, heterocyclic radical or heteroaryl.
The reaction that takes place is shown in formula (3):
Figure BDA0002475795990000171
in the present invention, M, L, R in the formula (3) 1 、R 2 、R 3 And the optional groups of X are respectively the same as M, L and R in the technical scheme 1 、R 2 、R 3 And the range of n is preferably the same as that of n in the technical scheme, and is not repeated.
The compound II, the organic base, the compound g and a sixth organic solvent are mixed, and a fifth acylation reaction is carried out under the anhydrous condition to obtain a compound h.
In the present invention, the organic base preferably includes triethylamine, pyridine or N, N-diisopropylethylamine. In the present invention, the compound g preferably includes an acid chloride, and more preferably includes p-nitrobenzoyl chloride. In the present invention, the molar ratio of the compound II, the organic base and the compound g is preferably 1: (1.5-5): (0.5 to 1.5), more preferably 1: (2-4): (0.6 to 1.2), most preferably 1: (2-3): (0.6-1.0).
In the present invention, the sixth organic solvent preferably includes dichloromethane, chloroform, 1, 2-dichloroethane, ethyl acetate, tetrahydrofuran, acetonitrile, dioxane, or acetone. In the present invention, the sixth organic solvent is preferably dried before use, and the drying method of the sixth organic solvent in the present invention is not particularly limited, and any drying method of an organic solvent known to those skilled in the art may be used. In the present invention, the ratio of the molar amount of the compound II to the volume of the sixth organic solvent is preferably 1mmol: (3-10) mL, more preferably 1mmol: (5-8) mL.
In the present invention, the mixing method is preferably stirring mixing, and the speed and time of stirring mixing are not particularly limited in the present invention, and the raw materials may be uniformly mixed. In the present invention, the mixing order is preferably that compound II, the organic base and the sixth organic solvent are mixed, and compound g is added dropwise under ice bath conditions. In the present invention, the compound g is preferably used in the form of a tetrahydrofuran solution of the compound g; the concentration of the tetrahydrofuran solution of the compound g is preferably 0.5 to 5mol/L, and more preferably 1 to 2mol/L. The dropping speed is not particularly limited in the invention, and the dropping can be carried out dropwise.
In the present invention, the temperature of the fifth acylation reaction is preferably-15 to 10 ℃, more preferably-10 to 5 ℃, and most preferably-5 to 0 ℃; the time of the fifth acylation reaction is preferably 4 to 12 hours, more preferably 5 to 10 hours, and most preferably 6 hours.
After the fifth acylation reaction, the method preferably further comprises the steps of adding water into a system of the fifth acylation reaction for first extraction to obtain a first organic phase and a water phase, adding an organic solvent for second extraction to obtain the water phase, combining the obtained second organic phase with the first organic phase, carrying out acid washing, water washing, saturated salt water washing and anhydrous magnesium sulfate drying on the combined organic phases in sequence, carrying out solid-liquid separation, and concentrating the obtained liquid phase component to obtain a compound h. The addition amount of the water is not particularly limited, and the added water can be separated from the organic phase in a liquid-liquid manner. In the present invention, the organic solvent used in the second extraction is preferably dichloromethane, and the amount of the organic solvent used in the present invention is not particularly limited, and may be any amount known to those skilled in the art. In the invention, the acid used for acid washing is preferably hydrochloric acid solution, and the concentration of the hydrochloric acid solution is preferably 1-2 mol/L; in the present invention, the number of times of the acid washing is not particularly limited, and the acid washing may be performed by an acid until the acid washing is acidic. In the present invention, the number of times of the washing is not particularly limited, and the washing may be carried out until the pH of the obtained washing liquid is neutral. The solid-liquid separation mode is not particularly limited, and a solid-liquid separation mode known to those skilled in the art can be adopted, such as suction filtration. The concentration method of the present invention is not particularly limited, and a concentration method known to those skilled in the art may be used, specifically, reduced pressure distillation, and the conditions of the reduced pressure distillation are not particularly limited, and distillation under reduced pressure is performed until no solvent flows out.
After the compound h is obtained, the compound h, palladium carbon and a seventh organic solvent are mixed in a hydrogen atmosphere, and reduction reaction is carried out under an anhydrous condition to obtain a compound j.
In the present invention, the seventh organic solvent preferably includes absolute ethanol, absolute methanol, isopropanol, dichloromethane, tetrahydrofuran, or n-hexane. In the present invention, the palladium carbon preferably contains palladium in an amount of 10wt%. In the present invention, the ratio of the molar amount of the compound h, the mass of palladium on carbon, and the volume of the seventh organic solvent is preferably 1mmol: (0.02-0.1) g: (5-20) mL, more preferably 1mmol: (0.04-0.0.08) g: (10-15) mL, most preferably 1mmol:0.06g:10mL.
Before the mixing, the invention preferably uses nitrogen to replace the air in the reaction vessel, and the replacement frequency is preferably 3 times; the nitrogen in the reaction vessel is then displaced with hydrogen, preferably 3 times.
In the present invention, the mixing method is preferably stirring mixing, and the speed and time of the stirring mixing are not particularly limited in the present invention, and the raw materials may be uniformly mixed.
In the present invention, the temperature of the reduction reaction is preferably 25 to 70 ℃, more preferably 40 to 60 ℃; the time for the reduction reaction is preferably 6 to 24 hours, more preferably 10 to 15 hours, and most preferably 12 hours.
After the reduction reaction, the method preferably further comprises cooling a system of the reduction reaction to room temperature, then carrying out solid-liquid separation, and concentrating the obtained liquid phase component to obtain a compound j. The cooling method of the present invention is not particularly limited, and a cooling method known to those skilled in the art may be used. The solid-liquid separation mode is not particularly limited, and a solid-liquid separation mode known to those skilled in the art can be adopted, such as suction filtration. The concentration method of the present invention is not particularly limited, and a concentration method known to those skilled in the art may be used, specifically, reduced pressure distillation, and the conditions of the reduced pressure distillation are not particularly limited, and distillation under reduced pressure is performed until no solvent flows out.
After the compound j is obtained, the compound j, phenyl chloroformate, an alkaline reagent and an eighth organic solvent are mixed, and a sixth acylation reaction is carried out under the anhydrous condition to obtain a compound k.
In the present invention, the alkaline agent preferably includes potassium carbonate, sodium carbonate, cesium carbonate or sodium hydrogen carbonate. In the present invention, the molar ratio of the compound j, the alkaline agent and phenyl chloroformate is preferably 1: (1-3): (1-2), more preferably 1: (1.5-2.5): (1.2 to 1.8), most preferably 1:1.5:1.5.
in the present invention, the eighth organic solvent preferably includes dichloromethane, chloroform, 1, 2-dichloroethane, ethyl acetate, tetrahydrofuran, acetonitrile, dioxane or acetone. In the present invention, the eighth organic solvent is preferably dried before use, and the drying method of the eighth organic solvent in the present invention is not particularly limited, and any drying method of an organic solvent known to those skilled in the art may be used. In the present invention, the ratio of the molar amount of the compound j to the volume of the eighth organic solvent is preferably 1mmol: (2-10) mL, more preferably 1mmol: (5-8) mL.
In the present invention, the mixing method is preferably stirring mixing, and the speed and time of stirring mixing are not particularly limited in the present invention, and the raw materials may be uniformly mixed. In the present invention, the mixing order is preferably that the compound j, the alkaline agent and the eighth organic solvent are mixed, and phenyl chloroformate is added dropwise under ice-bath conditions. The dropping speed is not particularly limited in the invention, and the dropping can be carried out dropwise.
In the present invention, the temperature of the sixth acylation reaction is preferably 40 to 75 ℃, more preferably 50 to 60 ℃; the time of the sixth acylation reaction is preferably 4 to 12 hours, more preferably 5 to 10 hours, and most preferably 8 hours.
After the sixth acylation reaction, the method preferably further comprises the steps of adding water into a system of the sixth acylation reaction, carrying out first solid-liquid separation, and washing and drying the obtained solid product in sequence to obtain a crude product k; and mixing the crude product k with a solvent, pulping, and performing second solid-liquid separation to obtain a compound k. In the present invention, the amount of water to be added is not particularly limited, and it is sufficient that no crystal is precipitated. The first solid-liquid separation and the second solid-liquid separation are not particularly limited in the present invention, and a solid-liquid separation method known to those skilled in the art may be adopted, specifically, suction filtration. The frequency of the acid washing is not specially limited, and the acid washing is carried out until no gas is generated. In the present invention, the drying temperature and time are not particularly limited, and the drying may be carried out until the weight is constant. In the present invention, the solvent for beating preferably includes diethyl ether, and the mass ratio of the compound j to diethyl ether is preferably 1: (1.5 to 5), more preferably 1: (2 to 4), most preferably 1:3. in the present invention, the purpose of the beating is to remove impurities.
After the compound k is obtained, the compound k, the compound III, the organic base and the ninth organic solvent are mixed and subjected to aminolysis reaction under anhydrous conditions to obtain the sEH inhibitor with the structure shown in the formula I.
In the present invention, the organic base preferably includes triethylamine, pyridine or N, N-diisopropylethylamine. In the present invention, the molar ratio of the compound k, the compound III and the organic base is preferably 1: (1-2): (1.5 to 5), more preferably 1: (1.1-1.8): (2 to 4), most preferably 1:1.1:2.
in the present invention, the ninth organic solvent preferably includes tetrahydrofuran, dioxane or acetonitrile. In the present invention, the ninth organic solvent is preferably dried before use, and the drying method of the ninth organic solvent in the present invention is not particularly limited, and an organic solvent drying method known to those skilled in the art may be used. In the present invention, the ratio of the molar amount of the compound k to the volume of the ninth organic solvent is preferably 1mmol: (5 to 20) mL, more preferably 1mmol: (10-15) mL.
In the present invention, the mixing method is preferably stirring mixing, and the speed and time of stirring mixing are not particularly limited in the present invention, and the raw materials may be uniformly mixed.
In the present invention, the temperature of the aminolysis reaction is preferably 40 to 80 ℃, more preferably 60 to 75 ℃; the time for the aminolysis reaction is preferably 4 to 12 hours, more preferably 5 to 10 hours, and most preferably 8 hours.
After the aminolysis reaction, the method preferably further comprises the steps of carrying out first solid-liquid separation after a system of the aminolysis reaction is cooled to room temperature to obtain a solid component and a liquid component, concentrating the liquid component, combining the obtained concentrate and the solid component, washing with tetrahydrofuran, carrying out second solid-liquid separation, and drying the obtained solid product to obtain the sEH inhibitor with the structure shown in the formula I. The cooling method of the present invention is not particularly limited, and a cooling method known to those skilled in the art may be used. The first solid-liquid separation and the second solid-liquid separation are not particularly limited in the present invention, and a solid-liquid separation method known to those skilled in the art may be adopted, specifically, suction filtration. The concentration method of the present invention is not particularly limited, and a concentration method known to those skilled in the art may be used, specifically, reduced pressure distillation, and the conditions of the reduced pressure distillation are not particularly limited, and distillation under reduced pressure is performed until no solvent flows out. In the present invention, the molar ratio of the tetrahydrofuran added for washing with tetrahydrofuran and the compound k is preferably (0.2 to 1): 1, more preferably (0.24 to 0.6): 1, most preferably 0.5. In the present invention, the tetrahydrofuran washing is preferably performed under stirring, the stirring speed in the present invention is not particularly limited, and a stirring speed well known to those skilled in the art may be used, and the stirring time is preferably 5 to 30min, more preferably 10 to 20min, and most preferably 10min. In the present invention, the drying temperature and time are not particularly limited, and the drying may be carried out to a constant weight.
The invention also provides application of the sEH inhibitor in the technical scheme or the sEH inhibitor prepared by the preparation method in the technical scheme in preparing a medicament for treating soluble epoxide hydrolase mediated diseases.
In the present invention, soluble cyclooxygenase inhibitors can increase the levels of EETs to exert their therapeutic effects. EETs inhibit the production of inflammatory arachidonic acid and cytokines through the Endoplasmic Reticulum (ER) stress pathway, convert the inflammatory arachidonic acid and cytokines from a wide activator of inflammatory chemical mediators and cell death systems into an homeostasis system maintaining the balance of mediators and metabolites, regulate and control the endoplasmic reticulum stress response to develop towards the direction of maintaining the balance in vivo and eliminating inflammation, and can promote the elimination of pathogenic microorganisms by organisms, which is completely different from the switch type anti-inflammatory action of conventional anti-inflammatory drugs, and the conventional anti-inflammatory drugs such as cyclooxygenase inhibitors and the like can reduce the expression of immune cell phagocytosis receptors CD11b and CD68 and the like to influence the elimination of pathogenic microorganisms by the organisms so as to increase infection. In addition, after the EETs are combined with the cell membrane EET receptors, various intracellular signal transduction pathways are activated to trigger functional reactions, such as MAPKs, PI3K-Akt, cAMP-PKA, src kinase and the like, and the functional reactions have better protective effects on organs such as heart, lung, kidney, brain and the like.
In the present invention, the sEH inhibitor is further preferably used for the preparation of a therapeutic agent for inflammatory diseases, pain, cardiovascular diseases, neurodegenerative diseases, diabetes and its complications, chronic nephritis, renal failure, chronic obstructive pulmonary disease, or pulmonary hypertension. In the present invention, the inflammatory disease preferably includes sepsis, cytokine storm, inflammatory bowel disease, chronic peptic ulcer or arthritis; the pain preferably comprises inflammatory pain or neuropathic pain; preferably, the neurodegenerative disease comprises stroke, parkinsonism or alzheimer's disease.
The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It should be apparent that the described embodiments are only some embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
EXAMPLE 1 Synthesis of N- (((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) -4-oxo-4- (piperidin-1-yl) butanamide, compound I-1
(1) Succinic anhydride (5 g,58.7 mmol) and dry dichloromethane (30 mL) were mixed with stirring, piperidine (5.9 g,58.7 mmol) was added dropwise under ice-water bath conditions, the first acylation reaction was carried out for 2h within 30min at 30 ℃, then dichloromethane was removed by concentration under reduced pressure, and ethyl acetate was added for recrystallization to give 4-oxo-4- (piperidin-1-yl) butyric acid (white solid, 8.8g, 95% yield).
(2) After 4-oxo-4- (piperidin-1-yl) butyric acid (0.5 g, 5.40mmol), EDCI (0.75g, 8.10mmol), HOBt (0.55g, 8.10mmol), triethylamine (1.35g, 27.0mmol) and dried dichloromethane (20 mL) were stirred at room temperature for 30min, memantine hydrochloride (0.39g, 5.40mmol) was added, and after the second acylation reaction for 4 hours, the reaction solution was poured into water (20 mL), extracted 3 times with dichloromethane (20 mL in volume each addition), and the resulting organic phase was washed with saturated sodium carbonate 2 times (20 mL in volume each addition), washed with water (20 mL), washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, suction-filtered, and concentrated to dryness under reduced pressure to give 1.2g of a white solid, and recrystallized by adding 2mL of propane to give Compound I-1 (white solid, 0.5g, 27% yield).
Characterization data for Compound I-1: the melting point is 102-103 ℃; 1 HNMR(400Hz,CDCl 3, GL-A102):δ(ppm)3.55(t,J＝5.2Hz,2H),3.42(t,J＝4.9Hz,2H),2.65(t,J＝6.6Hz,2H),2.53(br,2H),2.14-2.11(m,1H),1.83(d,J＝2.4Hz,2H),1.68-1.62(m,6H),1.58-1.51(m,4H),1.39-1.35(m,2H),1.29-1.26(m,2H),1.20-1.15(m,1H),1.13-1.10(m,1H),0.84(s,6H)；ESI MS m/z:347.3[M+H] + 。
example 2N 1 -cyclohexyl-N 4 Synthesis of (- ((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) succinimide, compound I-2
Preparation of Compound I-2 according to the procedure of example 1, differing from example 1 in that cyclohexylamine is substituted for piperidine in step (1) to give 4- (cyclohexylamino) -4-Oxobutyric acid (8.9 g, yield 90%); in step (2), 4- (cyclohexylamino) -4-oxobutanoic acid was substituted for 4-oxo-4- (piperidin-1-yl) butanoic acid to give compound I-2 (0.38 g, yield 45%). Characterization data for Compound I-2: the melting point is 128-130 ℃; 1 HNMR(400Hz,CDCl 3 ,GL-A102)δ(ppm)5.88(br,1H),5.67(br,1H),3.78-3.68(m,1H),2.46(br,4H),2.15-2.12(m,1H),1.90-1.86(m,2H),1.82(d,J＝2.3Hz,2H),1.72-1.66(m,2H),1.63(br,4H),1.60-1.58(m,1H),1.39-1.33(m,4H),1.30-1.26(m,3H),1.21-1.20(m,1H),1.19-1.10(m,4H),1.84(s,6H)；ESI MS m/z:361.3[M+H] + 。
example 3N 1 - (((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) -N 4 Synthesis of (E) -isobutylsuccinimide, compound I-3
Compound I-3 is prepared according to the procedure of example 1, except that isobutylamine is substituted for piperidine in step (1) to give 4- (isobutylamino) -4-oxobutanoic acid (8.0 g, 92% yield); in step (2), 4- (isobutylamino) -4-oxobutanoic acid was substituted for 4-oxo-4- (piperidin-1-yl) butanoic acid to give compound I-3 (0.40 g, yield 42%). Characterization data for Compound I-3: the melting point is 123-125 ℃; 1 HNMR(400Hz,CDCl 3 ,GL-A103)δ(ppm)6.16(br 1H),5.60(br,1H),3.06(q,J＝6.7,6.2Hz,2H),2.50-2.44(m,4H),2.14-2.11(m,1H),1.80(d,J＝2.7Hz,2H),1.79-1.72(m,1H),1.62(s,4H),1.38-1.35(m,2H),1.29-1.26(m,2H),1.19-1.14(m,2H),0.91(s,3H),0.90(s,3H),0.84(s,6H)；ESI MS m/z:355.3[M+Na] + 。
example 4 Synthesis of (Z) -N- (((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) -4-oxo-4- (piperidin-1-yl) but-2-enamide, compound I-4
Compound I-4 was prepared according to the procedure of example 1, except that maleic anhydride was substituted for succinic anhydride in step (1) to give (Z) -4-oxo-4- (piperidin-1-yl) but-2-enoic acid (7.9 g, yield 85%); in step (2), (Z) -4-oxo-4- (piperidin-1-yl) but-2-enoic acid instead of 4-oxo-4- (piperidin-1-yl) butanoic acid gave compound I-4 (0.10 g, 11% yield). Characterization data for Compound I-4: the melting point is 162-164 ℃; 1 H NMR(400Hz,CDCl 3 ,GL-A201)δ(ppm)7.35(br,1H),6.26(d,J＝12.9Hz,1H),5.97(d,J＝12.5Hz,1H),3.61(t,J＝5.6Hz,2H),3.42(t,J＝5.5Hz,2H),2.15-2.12(m,1H),1.85(d,J＝2.0Hz,2H),1.70-1.54(m,10H),1.40-1.37(m,2H),1.29-1.26(m,2H),1.20-1.10(m,2H),0.85(s,6H)；ESI MS m/z:345.3[M+H] + 。
example 5N 1 -cyclohexyl-N 4 - ((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) fumaramide, synthesis of Compound I-5
Compound I-5 is prepared according to the procedure of example 1, except that in step (1), maleic anhydride is substituted for succinic anhydride and cyclohexylamine is substituted for piperidine to give (E) -4- (cyclohexylamino) -4-oxobut-2-enoic acid (8.6 g, 86% yield); in step (2), (E) -4- (cyclohexylamino) -4-oxobut-2-enoic acid instead of 4-oxo-4- (piperidin-1-yl) butanoic acid was obtained to give Compound I-5 (0.31 g, yield 34%). Characterization data for Compound I-5: the melting point is 234-236 ℃; 1 HNMR(400Hz,CDCl 3 ,GL-A202)δ(ppm)6.84(d,J＝14.8Hz,1H),6.76(d,J＝14.8Hz,1H),5.81(d,J＝7.6Hz,1H),5.72(br,1H),3.89-3.81(m,1H),2.18-2.14(m,1H),1.96-1.92(m,2H),1.87(d,J＝2.7Hz,2H),1.76-1.69(m,6H),1.65-1.60(m,1H),1.43-1.29(m,6H),1.23-1.13(m,5H),0.86(s,6H)；ESI MS m/z:359.3[M+H] + 。
example 6N 1 - ((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) -N 4 Synthesis of isobutyl fumaroyl, compound I-6
Compound I-6 was prepared according to the procedure of example 1, except that in step (1), maleic anhydride was substituted for succinic anhydride and isobutylamine was substituted for piperidine to give (E) -4- (isobutylamino) -4-oxobut-2-enoic acid (7.7 g, yield 88%); in step (2), (E) -4- (isobutylamino) -4-oxobut-2-enoic acid instead of 4-oxo-4- (piperidin-1-yl) butanoic acid gave compound I-6 (0.34 g, yield 35%). Characterization data for Compound I-6: the melting point is 97-99 ℃; 1 HNMR(400Hz,CDCl 3 ,GL-A203)δ(ppm)7.36(br,1H),6.03(d,J＝14.0Hz,1H),6.01(q,J＝14.0Hz,1H),3.15(t,J＝5.7Hz,2H),2.7-2.15(m,1H),1.89(br,2H),1.73-1.68(m,2H),1.65-1.63(m,1H),1.42-1.39(m,2H),1.32-1.29(m,2H),1.28-1.24(m,2H),1.21-1.13(m,2H),0.96(s,3H),0.95(s,3H),0.86(s,6H)；ESI MS m/z:333.3[M+H] + 。
EXAMPLE 7 Synthesis of N- (((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) -5-oxo-5- (piperidin-1-yl) pentanamide, compound I-7
Compound I-7 was prepared according to the procedure of example 1, except that glutaric anhydride was substituted for succinic anhydride in step (1) to give 5-oxo-5- (piperidin-1-yl) pentanoic acid (8.1 g, 93% yield); in step (2), 5-oxo-5- (piperidin-1-yl) pentanoic acid was used instead of 4-oxo-4- (piperidin-1-yl) butanoic acid to give compound I-7 (0.34 g, 38% yield). Characterization data for Compound I-7: the melting point is 98-100 ℃; 1 HNMR(400Hz,CDCl 3 ,GL-A301)δ(ppm)5.65(br,1H),3.54(t,J＝5.4Hz),3.40(t,J＝5.4Hz,2H),2.40(t,J＝7.0Hz,2H),2.18(t,J＝7.1Hz,2H),2.14-2.11(m,1H),1.67-1.62(m,6H),1.58-1.52(m,4H),1.40-1.35(m,2H),1.29-1.26(m,2H),1.20-1.10(m,2H),0.84(s,6H)；ESI MS m/z:361.3[M+H] + 。
example 8N 1 -cyclohexyl-N 5 Synthesis of (- ((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) glutaramide, compound I-8
Compound I-8 was prepared according to the procedure of example 1, except that glutaric anhydride was substituted for succinic anhydride and cyclohexylamine was substituted for piperidine in step (1) to give 5- (cyclohexylamino) -5-oxopentanoic acid (8.8 g, 95% yield); in step (2), 5- (cyclohexylamino) -5-oxopentanoic acid was used instead of 4-oxo-4- (piperidin-1-yl) butanoic acid to give compound I-8 (0.35 g, 40% yield). Characterization data for Compound I-8: the melting point is 155-157 ℃; 1 HNMR(400Hz,CDCl 3 ,GL-A302)δ(ppm)5.72(s,1H),5.51(br,1H),3.80-3.71(m,1H),2.23(t,J＝7.1Hz,2H),2.17(t,J＝7.0Hz,2H),2.14-2.12(m,1H),1.94-1.87(m,4H),1.82(d,J＝2.5Hz,2H),1.73-1.67(m,2H),1.64(s,4H),1.61-1.60(m,1H),1.41-1.34(m,4H),1.32-1.27(m,2H),1.22-1.09(m,5H),0.85(s,6H)；ESI MS m/z:375.4[M+H] + 。
example 9N 1 - ((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) -N 5 Synthesis of isobutyl glutaramide, compound I-9
Compound I-9 was prepared according to the procedure of example 1, except that in step (1), glutaric anhydride was substituted for succinic anhydride and isobutylamine was substituted for piperidine to give 5- (isobutylamino) -5-oxopentanoic acid (7.4 g, 90% yield); in step (2), 5- (isobutylamino) -5-oxopentanoic acid was used instead of 4-oxo-4- (piperidin-1-yl) butyric acid to give compound I-8 (0.39 g, 42% yield). Characterization data for Compound I-8: the melting point is 130-132 ℃; 1 H NMR(400Hz,CDCl 3 ,GL-A303)δ(ppm)5.86(br,1H),5.45(br,1H),3.07(dd,J＝6.7Hz,6.1Hz,2H),2.27(t,J＝7.1Hz,2H),2.17(t,J＝7.4Hz,2H),2.14-2.12(m,1H),1.95-1.88(m,2H),1.82(d,J＝2.9Hz,2H),1.80-1.73(m,1H),1.64(s,4H),1.39-1.36(m,2H),1.30-1.27(m,2H),1.20-1.11(m,2H),0.92(s,3H),0.91(s,3H),0.85(s,6H).349.3[M+H] + 。
EXAMPLE 10 Synthesis of N- (((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) -4- (piperidine-1-carbonyl) benzamide, compound I-10
(1) Monomethyl terephthalate (18g, 0.1mol), thionyl chloride (75 mL) and DMF (0.5 mL) were stirred and mixed, heated to 80 ℃ and refluxed for substitution reaction for 2 hours, and excess thionyl chloride was removed by distillation under reduced pressure and cooled to room temperature to give methyl 4- (chlorocarbonyl) benzoate (pale yellow solid, 19.4g, 98% yield).
(2) Memantine hydrochloride (5.4 g, 25.0mmol), triethylamine (12.6 g, 0.13mol), DMAP (0.56g, 5.0mmol) and dry dichloromethane (30 mL) were mixed, after cooling to 0 ℃ in an ice bath, a dichloromethane solution of methyl 4- (chlorocarbonyl) benzoate (9.9 g,50.0mmol, 2.5mol/L) was added dropwise, after completion of dropwise addition, the third acylation reaction was carried out at room temperature for 8 hours, the resulting reaction solution was poured into water (40 mL), dichloromethane was added and extracted 3 times (30 mL in volume each addition), saturated sodium carbonate was washed 2 times (30 mL in volume each addition), water (30 mL), saturated brine was washed (30 mL), anhydrous magnesium sulfate was dried, suction filtration and concentrated under reduced pressure to obtain methyl 4- (((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) carbamoyl) benzoate (white solid, 4.8g, yield 56%).
(3) Methyl 4- (((1r, 3r,5s, 7r) -3, 5-dimethyladamantan-1-yl) carbamoyl) benzoate (3g, 8.79mmol), THF (30 mL), water (21 mL) and inorganic base monohydrate (1.11g, 26.4mmol) were mixed, reacted at 25 ℃ for 3 hours at room temperature, filtered, the resulting liquid component was concentrated to dryness under reduced pressure, water (40 mL) was added to the resulting concentrate, the pH was adjusted to 1 with 1mol/L hydrochloric acid solution under ice bath conditions, filtered, and the resulting solid component was washed with water and dried to give 4- (((1r, 3r,5s, 7r) -3, 5-dimethyladamantan-1-yl) carbamoyl) benzoic acid (white solid, 2.7g, yield 94%).
(4) 4- (((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) carbamoyl) benzoic acid (0.3g, 0.92mmol), EDCI (0.26g, 1.38mmol), HOBt (0.19g, 1.38mmol), triethylamine (0.46g, 4.58mmol) and dry THF (20 mL) were stirred at room temperature for 30min, piperidine (94mg, 1.10mmol) was added, the reaction mixture was heated to 40 ℃ and then subjected to a fourth acylation reaction for 12h, poured into water (20 mL), extracted with dichloromethane 3 times (20 mL in volume each addition), washed with water (20 mL), washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, suction filtered, and concentrated to dryness under reduced pressure to give 1.2g of a white solid, and recrystallized from acetone to give Compound I-10 (white solid, 0.2g, 56% yield). Characterization data for Compound I-10: the melting point is 148-150 ℃; 1 HNMR(400Hz,CDCl 3 ,GL-A401)δ(ppm)7.73(d,J＝8.2Hz,2H),7.42(d,J＝8.2Hz,2H),5.83(s,1H),3.68(br,2H),3.31(br,2H),2.21-2.18(m,1H),1.96(d,J＝2.2Hz,2H),1.81-1.73(m,4H),1.67(br,6H),1.45-1.32(m,4H),1.26-1.16(m,2H),0.59(s,6H)。
example 11N 1 -cyclohexyl-N 4 - ((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) terephthalamide, synthesis of Compound I-11
Compound I-11 is prepared according to the procedure of example 10, step (4), differing from example 10 in that cyclohexylamine is substituted for piperidine in step (4), giving compound I-11 (0.21 g, 57% yield). Characterization data for Compound I-11: the melting point is 257-259 ℃; 1 HNMR(400Hz,CDCl 3 ,GL-A402)δ(ppm)7.76(q,J＝14.6,8.7Hz,4H),6.00(d,J＝7.9Hz,1H),5.84(s,1H),2.21-2.19(m,1H),2.06-2.02(m,2H),1.97(d,J＝2.0Hz,2H),1.81-1.75(m,6H),1.69-1.64(m,1H),1.48-1.30(m,6H),1.28-1.17(m,5H),0.89(s,6H)。
example 12N 1 - ((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) -N 4 Synthesis of (E) -isobutylterephthalamide, compound I-12
Compound I-12 is prepared according to the procedure of example 10, step (4), differing from example 10 in that isobutylamine is substituted for piperidine in step (4) to give compound I-12 (0.21 g, 60% yield). Characterization data for Compound I-12: the melting point is 234-236 ℃; 1 HNMR(400Hz,CDCl 3 ,GL-A403)δ(ppm)7.76(q,J＝16.7,8.1Hz,4H),6.22(br,1H),5.85(br,1H),3.30(t,J＝6.2Hz,2H),2.21-2.19(m,1H),1.97(d,J＝2.2Hz,2H),1.95-1.88(m,1H),1.82-1.74(m,4H),1.46-1.32(m,4H),1.26-1.17(m,2H),0.99(s,3H),0.98(s,3H),0.89(s,6H)。
example Synthesis of 131- ((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) -3- (4- (piperidine-1-carbonyl) phenyl) urea, compound I-13
(1) Piperidine (6.88g, 80.8mmol), triethylamine (16.4g, 0.16mol) and dichloromethane (25 mL) are mixed, p-nitrobenzoyl chloride (10.0 g, 53.9mmol) is added dropwise under ice bath conditions, after dropwise addition, the temperature is naturally raised to 25 ℃ and then a fifth acylation reaction is carried out for 6h, the reaction liquid is poured into water for extraction, a first organic phase and an aqueous phase are obtained, the aqueous phase is extracted for 2 times (30 mL in volume for each addition) by dichloromethane, a second organic phase is obtained, after the first organic phase and the second organic phase are combined, washing for 2 times (30 mL in volume for each addition) by 1mol/L hydrochloric acid solution is carried out, washing for 2 times (30 mL in volume for each addition), saturated brine washing (30 mL), anhydrous magnesium sulfate drying, suction filtration and vacuum concentration are carried out to dryness to obtain a light yellow oily substance, diethyl ether (30 mL) is added, and then pulping is carried out to obtain (4-nitrophenyl) (piperidin-1-yl) methanone (10 g, 53% yield).
(2) (4-Nitrophenyl) (piperidin-1-yl) methanone (10g, 42.7mmol), anhydrous ethanol (100 mL), and 10wt% Pd-C (0.25g, 0.24mmol) were mixed, the reaction vessel was replaced with argon gas three times, then replaced with hydrogen gas three times, the reduction reaction was stirred at 50 ℃ for 12 hours, after cooling to room temperature, suction filtration was conducted, concentration under reduced pressure to dryness, and (4-aminophenyl) (piperidin-1-yl) methanone (white solid, 8.0g, yield 92%) was obtained.
(3) (4-aminophenyl) (piperidin-1-yl) methanone (5.5 g,26.9 mmol), potassium carbonate (5.6 g,40.4 mmol) and methylene chloride (20 mL) were mixed, phenyl chloroformate (11.0 g,35.3 mmol) was slowly added dropwise under ice-bath conditions, after completion of addition, the reaction mixture was subjected to a sixth acylation reaction at room temperature for 7 hours, and the reaction mixture was poured into water to precipitate a large amount of solid, which was then subjected to suction filtration, water washing and drying to give 7.2g of a white solid, and diethyl ether (10 mL) was added thereto, and then subjected to suction filtration after beating to give phenyl (4- (piperidin-1-carbonyl) phenyl) carbamate (white solid, 6.4g, yield 74%).
(4) Phenyl (4- (piperidine-1-carbonyl) phenyl) carbamate (0.5g, 1.54mmol), memantine (0.30g, 1.70mmol), triethylamine (0.31g, 3.08mmol) and redistilled tetrahydrofuran (5 mL) were mixed, aminolyzed at 75 ℃ for 8h, cooled to room temperature, filtered with suction, rinsed with tetrahydrofuran, and dried to give compound I-13 (white solid, 0.41g, 65% yield). Characterization data for Compound I-13: the melting point is 204-205 ℃; 1 HNMR(400Hz,CDCl 3 ,GL-B401)δ(ppm)8.41(s,1H),7.37(d,J＝8.6Hz,2H),7.22(d,J＝8.6Hz,2H),5.95(s,1H),3.42(br,4H),2.10-2.08(m,1H),1.76-1.75(m,2H),1.61-1.55(m,6H),1.49(br,4H),1.35-1.24(m,4H),1.12(s,2H),0.83(s,6H)。
example 14 Synthesis of N-cyclohexyl-4- (3- (((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) ureido) benzamide, compound I-14
Compound I-14 was prepared according to the procedure for example 13, except that cyclohexylamine was used instead of piperidine in step (1) to give N-cyclohexyl-4-nitrobenzamide (9.0 g, 60% yield); replacing (4-nitrophenyl) (piperidin-1-yl) methanone with N-cyclohexyl-4-nitrobenzamide in step (2) to give 4-amino-N-cyclohexylbenzamide (7.8 g, 98% yield); substituting 4-amino-N-cyclohexylbenzamide for (4-aminophenyl) (piperidin-1-yl) methanone in step (3) gave phenyl (4- (cyclohexylcarbamoyl) phenyl) carbamate (0.78 g, 29.5% yield); phenyl (4- (cyclohexylcarbamoyl) phenyl) carbamate instead of phenyl (4- (piperidine-1-carbonyl) phenyl) carbamate in step (4) gave compound I-14 (0.60 g, 62% yield). Characterization data for Compound I-14: has a melting point of>300℃； 1 H NMR(400Hz,DMSO-d 6 ,GL-B402)δ(ppm)8.47(s,1H),7.94(d,J＝8.0Hz,2H),7.71(d,J＝8.7Hz,2H),7.77(d,J＝8.7Hz,2H),5.97(s,1H),3.73-3.72(m,1H),2.10-2.08(m,1H),1.79-1.73(m,6H),1.61-1.58(m,5H),1.34-1.25(m,8H),1.15-1.09(m,3H),0.83(s,6H)。
Example 154 Synthesis of- (3- ((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) ureido) -N-isobutylbenzamide, compound I-15
Compound I-15 is prepared according to the procedure of example 13, except that in step (1), isobutylamine is substituted for piperidine to give N-isobutyl-4-nitrobenzamide (6.0 g, 100% yield); substituting N-isobutyl-4-nitrobenzamide for (4-nitrophenyl) (piperidin-1-yl) methanone in step (2) to give 4-amino-N-isobutylbenzamide (5.2 g, 100% yield); substituting 4-amino-N-isobutylbenzamide for (4-aminophenyl) (piperidin-1-yl) methanone in step (3) gave phenyl (4- (isobutylcarbamoyl) phenyl) carbamate (4.4 g, 52% yield); phenyl (4- (isobutylcarbamoyl) phenyl) carbamate instead of phenyl (4- (piperidine-1-carbonyl) phenyl) carbamate in step (4) gave compound I-15 (0.33 g, 67% yield). Characterization data for Compound I-15: melting point of>300℃； 1 HNMR(400Hz,DMSO-d 6 ,GL-B403)δ(ppm)8.68(s,1H),8.22(t,J＝5.8Hz,1H),7.72(d,J＝8.8Hz,2H),7.38(J＝7.1Hz,2H),6.13(s,1H),3.05(t,J＝6.1Hz,2H),2.10-2.08(m,1H),1.86-1.79(m,1H),1.76-1.75(m,2H),1.62-1.55(m,4H),1.35-1.24(m,4H),1.12(s,2H),0.88(s,3H),0.86(s,3H),0.83(s,6H)。
Example 16N 1 - (1- (((3r, 5r, 7r) -adamantan-1-yl) ethyl) -N 4 Synthesis of (E) -isobutylsuccinimide, compound I-16
Compound I-16 was prepared according to the procedure of step (2) of example 3, except for using rimantadine hydrochloride in place of memantine hydrochloride in step (2) of example 3, to give compound I-16 (0.20 g, yield 21%). Characterization data for Compound I-16: the melting point is 186-188 ℃; 1 HNMR(400Hz,CDCl 3 ,gL-C103)δ(ppm)6.24(br,1H),5.94(br,1H),3.71-3.63(m,1H),3.13-3.00(m,2H),2.60-2.49(m,4H),1.97(br,3H),1.80-1.74(m,1H),1.72-1.60(m,6H),1.54-1.45(m,6H),1.00(d,J＝6.9Hz,3H),0.90(d,J＝6.7Hz,6H)。
example 17N 1 - (1- ((3r, 5r, 7r) -adamantan-1-yl) ethyl) -N 5 Synthesis of isobutyl glutaramide, compound I-17
Compound I-17 is prepared according to the procedure of step (2) of example 9, except that rimantadine hydrochloride is substituted for memantine hydrochloride in step (2) of example 9, to give compound I-17 (0.18 g, 45% yield). Characterization data for Compound I-17: the melting point is 191-193 ℃; 1 HNMR(400Hz,CDCl 3 ,gL-C303)δ(ppm)5.95(br,1H),5.66(br,1H),3.74-3.67(m,1H),3.08(t,J＝6.6Hz,2H),2.31-2.27(m,4H),2.00-1.94(m,5H),1.82-1.74(m,1H),1.72-1.60(m,6H),1.55-1.46(m,6H),1.01(d,J＝6.9Hz,3H),0.92(d,J＝6.7Hz,6H)。
EXAMPLE 181- (1- (((1s, 3s) -adamantan-1-yl) ethyl) -3- (4- (piperidine-1-carbonyl) phenyl) urea, synthesis of Compound I-18
Compound I-18 is prepared according to the procedure of step (4) of example 13, except that memantine is replaced with rimantadine in step (4) to give compound I-18 (0.24 g, 62% yield) in example 13.
Characterization data for Compound I-18: the melting point is 181-183 ℃; 1 HNMR(400Hz,DMSO-d 6 ,gL-C401)δ(ppm)8.50(s,1H),7.41(d,J＝8.6Hz,2H),6.02(d,J＝9.4Hz,1H),3.42-3.34(m,5H),1.96(br,3H),1.69-1.58(m,8H),1.55-1.45(m,10H),0.97(d,J＝6.8Hz,3H)。
EXAMPLE 194 Synthesis of- (3- (1- (((1s, 3s) -adamantan-1-yl) ethyl) ureido) -N-cyclohexylbenzamide, compound I-19
Compound I-19 is prepared according to the procedure of step (4) of example 14, except that memantine is replaced with rimantadine in step (4) to give compound I-19 (0.24 g, 64% yield). Characterization data for Compounds I-19: the melting point is 280-283 ℃; 1 HNMR(400Hz,DMSO-d 6 ,gL-C402)δ(ppm)8.58(s,1H),7.94(d,J＝7.9Hz,1H),7.72(d,J＝8.7Hz,2H),7.41(d,J＝8.8Hz,2H),6.06(d,J＝9.4Hz,1H),3.74-3.72(m,1H),3.42-3.34(m,1H),2.00(br,3H),1.79-1.72(m,4H),1.69-1.58(m,7H),1.55-1.45(m,6H),1.35-1.24(m,4H),0.97(d,J＝6.8Hz,3H)。
EXAMPLE 204 Synthesis of 3- (1- (((1s, 3s) -adamantan-1-yl) ethyl) ureido) -N-isobutylbenzamide, compound I-20
Compound I-20 is prepared according to the procedure of step (4) of example 15, except that memantine is replaced with rimantadine in step (4) to give compound I-20 (0.23 g, 60% yield). Characterization data for Compound I-20: the melting point is 207-209 ℃; 1 HNMR(400Hz,DMSO-d 6 ,gL-C403)δ(ppm)8.59(s,1H),8.21(t,J＝5.7Hz,1H),7.73(d,J＝8.8Hz,2H),7.42(d,J＝8.8Hz,2H),6.08(d,J＝9.3Hz,1H),3.42-3.34(m,1H),3.05(t,J＝6.1Hz,2H),1.96(br,3H),1.86-1.76(m,1H),1.69-1.58(m,6H),1.55-1.45(m,6H),0.97(d,J＝6.8Hz,3H),0.88(d,J＝6.7Hz,6H)。
example 21N 1 - (((1S, 2R, 5R) -adamantan-2-yl) -N 5 Synthesis of isobutyl glutaramide, compound I-21
Compound I-21 was prepared according to the procedure of step (2) of example 2, except that 2-amantadine was used instead of memantine hydrochloride in step (2), to give compound I-21 (0.23 g, yield 44%). Characterization data for Compound I-21: the melting point is 186-188 ℃; 1 HNMR(400Hz,DMSO-d 6 ,gL-D303)δ(ppm)7.74(t,J＝5.4Hz,1H),7.64(t,J＝7.5Hz,2H),3.83(d,J＝7.3Hz,1H),2.85(t,J＝6.2Hz,2H),2.13(t,J＝7.4Hz,2H),2.06(t,J＝7.4Hz,2H),1.99-1.95(m,2H),1.79-1.62(m,13H),1.48-1.45(m,2H)。
example Synthesis of 221- ((1S, 2R, 5R) -adamantan-2-yl) -3- (4- (piperidine-1-carbonyl) phenyl) urea, compound I-22
Compound I-22 was prepared according to the procedure of example 13, step (4), differing from example 13 in that 2-amantadine was used instead of memantine in step (4), giving compound I-22 (0.24 g, 68% yield). Characterization data for Compound I-22: the melting point is 265-267 ℃; 1 H NMR(400Hz,DMSO-d 6 ,gL-D401)δ(ppm)8.58(s,1H),7.42-7.39(m,2H),7.26-7.23(m,2H),6.50(d,J＝8.0Hz,1H),3.77(d,J＝7.8Hz,1H),3.43(br,4H),1.87-1.74(m,10H),1.70-1.49(m,10H)。
example 234- (3- (((1S, 2R, 5R) -adamantan-2-yl) ureido) -N-cyclohexylbenzamide, synthesis of Compound I-23
Compound I-23 was prepared according to the procedure of example 14, step (4), except that 2-amantadine was used instead of memantine in step (4) to give compound I-23 (0.23 g, 66% yield). Characterization data for Compound I-23: has a melting point of>300℃； 1 HNMR(400Hz,DMSO-d 6 ,gL-D402)δ(ppm)8.67(s,1H),7.94(d,J＝8.0Hz,1H),7.73(d,J＝8.7Hz,2H),7.41(d,J＝8.8Hz,2H),6.54(d,J＝8.0Hz,1H),3.78-3.72(m,2H),1.87-1.71(m,16H),1.62-1.55(m,3H),1.34-1.24(m,4H),1.15-1.10(m,1H)。
EXAMPLE 244 Synthesis of- (3- (((1S, 2R, 5R) -adamantan-2-yl) ureido) -N-isobutylbenzamide, compound I-24
Compound I-24 was prepared according to the procedure of example 15, step (4), except that 2-amantadine was used instead of memantine in step (4) to give compound I-24 (0.25 g, yield 70%). Characterization data for Compound I-24: the melting point is 270-272 ℃; 1 HNMR(400Hz,DMSO-d 6 ,gL-D403)δ(ppm)8.88(s,1H),8.22(t,J＝5.7Hz,1H),7.73(d,J＝8.7Hz,2H),7.44(d,J＝8.7Hz,2H),6.69(d,J＝8.0Hz,1H),3.78-3.77(m,2H),3.05(t,J＝6.2Hz,2H),1.91-1.70(m,13H),1.57-1.54(m,2H),0.88(d,J＝6.7Hz,6H)。
example 25N 1 - ((5s, 7s) -5-hydroxyadamantan-2-yl) -N 5 Synthesis of isobutyl glutaramide, compound I-25
Compound I-25 was prepared according to the procedure of example 9, step (4), differing from example 9 in that in step (4), trans-4-amino-1-adamantanol was substituted for memantine hydrochloride to give compound I-25 (0.45 g, 50% yield). Characterization data for Compound I-25: the melting point is 181-183 ℃; 1 HNMR(400Hz,DMSO-d 6 ,gL-E303)δ(ppm)7.74(t,J＝5.5Hz,1H),7.59(d,J＝7.4Hz,1H),4.37(s,1H),3.76-3.74(m,1H),2.85(t,J＝6.1Hz,2H),2.12(t,J＝7.4Hz,2H),2.06(t,J＝7.4Hz,2H),1.97(br,1H),1.88-1.84(m,4H),1.73-1.63(m,5H),1.62-1.56(m,4H),1.31-1.28(m,2H),0.82(d,J＝6.7Hz,6H)。
example 261- ((5s, 7 s) -5-hydroxyadamantan-2-yl) -3- (4- (piperidine-1-carbonyl) phenyl) urea, synthesis of Compound I-26
Compound I-26 was prepared according to the procedure of example 13, step (4), differing from example 13 in that trans-4-amino-1-adamantanol was used instead of memantine in step (4), giving compound I-26 (0.25 g, 69% yield). Characterization data for Compound I-26: the melting point is 270-272 ℃; 1 HNMR(400Hz,DMSO-d 6 ,gL-E401)δ(ppm)8.58(s,1H),7.42(d,J＝8.6Hz,2H),7.25(d,J＝8.6Hz,2H),6.44(d,J＝7.8Hz,1H),4.41(s,1H),3.71-3.69(m,1H),3.43(br,4H),2.03(br,1H),1.93(br,2H),1.76-1.62(m,10H),1.49-1.34(m,6H)。
EXAMPLE 27 Synthesis of N-cyclohexyl-4- (3- (((5s, 7s) -5-hydroxyadamantan-2-yl) ureido) benzamide, compound I-27
Compound I-27 was prepared according to the procedure of example 14, step (4), except that in step (4), trans-4-amino-1-adamantanol was used instead of memantine to give compound I-27 (0.27 g, yield 75%). Characterization data for Compound I-27: melting point of>300℃； 1 HNMR(400Hz,DMSO-d 6 ,gL-E402)δ(ppm)8.63(s,1H),7.94(d,J＝7.9Hz,1H),7.73(d,J＝8.7Hz,2H),7.41(d,J＝8.7Hz,2H),6.45(d,J＝7.8Hz,1H),4.41(s,1H),3.71-3.69(m,2H),2.03(br,1H),1.93(br,2H),1.79-1.68(m,8H),1.64-1.62(m,5H),1.45-1.38(m,2H),1.34-1.23(m,4H),1.17-1.10(m,1H)。
Example 284- (3- ((5s, 7 s) -5-hydroxyadamantan-2-yl) ureido) -N-isobutylbenzamide, synthesis of Compound I-28
Compound I-28 was prepared according to the procedure of example 15, step (4), differing from example 15 in that trans-4-amino-1-adamantanol was used instead of memantine in step (4), giving compound I-28 (0.27 g, yield 72%). Characterization data for Compound I-28: the melting point is 270-272 ℃; 1 HNMR(400Hz,DMSO-d 6 ,gL-E403)δ(ppm)8.65(s,1H),8.22(t,J＝5.6Hz,1H),7.74(d,J＝8.6Hz,2H),7.42(d,J＝8.6Hz,2H),6.47(d,J＝7.7Hz,1H),4.42(s,1H),3.72-3.70(m,1H),3.05(t,J＝6.3Hz,2H),2.03(br,1H),1.94(br,2H),1.86-1.81(m,1H),1.79-1.57(m,9H),1.41-1.38(m,2H),0.87(d,J＝7.4Hz,6H)。
EXAMPLE 291- (((1r, 3s,5R, 7S) -3-hydroxyadamantan-1-yl) -3- (4- (piperidine-1-carbonyl) phenyl) urea, synthesis of Compound I-29
Compound I-29 was prepared according to the procedure of example 13, step (4), except that 3-amino-1-adamantanol was used instead of memantine in step (4) to give compound I-29 (0.27 g, 73% yield). Characterization data for Compound I-29: the melting point is 245-247 ℃; 1 HNMR(400Hz,DMSO-d 6 ,gL-F401)δ(ppm)8.42(s,1H),7.37(d,J＝8.5Hz,2H),7.23(d,J＝8.6Hz,2H),6.00(s,1H),4.80(s,1H),3.42(br,4H),2.14(br,2H),1.85-1.42(m,6H),1.61-1.42(m,12H)。
example 30 Synthesis of N-cyclohexyl-4- (3- (((1r, 3s,5R, 7S) -3-hydroxyadamantan-1-yl) ureido) benzamide, compound I-30
Compound I-30 was prepared according to the procedure of example 13, step (4), except that 3-amino-1-adamantanol was used instead of memantine in step (4) to give compound I-30 (0.26 g, yield 71%). Characterization data for Compound I-30: the melting point is 263-265 ℃; 1 HNMR(400Hz,DMSO-d 6 ,gL-F402)δ(ppm)8.54(s,1H),7.94(d,J＝7.9Hz,1H),7.72(d,J＝8.8Hz,2H),7.37(d,J＝8.8Hz,2H),6.08(s,1H),4.48(s,1H),3.74-3.72(m,1H),2.14(br,2H),1.85-1.77(m,8H),1.73-1.72(m,2H),1.61-1.51(m,5H),1.47-1.42(m,2H),1.35-1.24(m,4H),1.13-1.10(m,1H)。
example 314- (3- ((1r, 3s,5R, 7S) -3-hydroxyadamantan-1-yl) ureido) -N-isobutylbenzamide, synthesis of Compound I-31
Compound I-31 was prepared according to the procedure of example 15, step (4), differing from example 15 in that 3-amino-1-adamantanol was used instead of memantine in step (4), giving compound I-31 (0.29 g, 74% yield). Characterization data for Compound I-31: the melting point is 156-158 ℃; 1 HNMR(400Hz,DMSO-d 6 ,gL-F403)δ(ppm)8.48(s,1H),8.22(t,J＝5.7Hz,1H),7.72(d,J＝8.8Hz,2H),7.38(d,J＝8.8Hz,2H),6.03(s,1H),4.49(s,1H),3.05(t,J＝6.6Hz,2H),2.14(br,2H),1.85-1.76(m,7H),1.57-1.42(m,6H),0.87(d,J＝6.7Hz,6H)。
test for inhibitory Activity of example Compounds I-1 to I-31 on sEH enzyme
The detection principle is as follows: a specific substrate (3-phenyl-oxy) -acetic acid cyano- (6-methoxy-naphthalene-2-yl) methyl ester, namely PHOME (chemical industry, anAb Keumann, mich) does not have fluorescence per se, but is hydrolyzed under the action of sEH enzyme to generate a product 6-methoxy-2-naphthaldehyde, and the 6-methoxy-2-naphthaldehyde can emit fluorescence with the wavelength of 465nm under the excitation of 330nm light waves. The strength of the detected fluorescence signal is inversely proportional to the strength of the inhibition effect on the sEH enzyme. According to the above principle, the enzyme activity of sEH was measured by a reaction rate method. And selecting a section closest to the straight line in the initial stage on the reaction curve, and calculating the initial reaction speed Vmax (indicating the enzyme activity level). Vmax of the enzyme treated with each sample was determined, and then compared with a normal control to calculate the percent inhibition of compounds I-1 to I-31. And continuously reading the fluorescence signal intensity value at each time point in a kinetic monitoring mode to represent the generation amount of the product, wherein the generation rate of the product can reflect the activity of the enzyme according to an enzyme reaction rate method.
Respectively dissolving compounds to be tested (compounds I-1-I-31) in dimethyl sulfoxide to obtain a solution of the compounds to be tested with the storage concentration of 20mM, storing the solution of the compounds to be tested in a refrigerator at the temperature of-20 ℃, and diluting the solution of the compounds to be tested with DMSO before use, wherein mM is mmol/L.
The instrument comprises the following steps: spectramax, 96-well plate (black), 0.2-2.0 muL, 20-200 muL, 100-1000 muL pipetting gun, 30-300 muL multi-channel pipette, plastic groove, ice box.
Reagent: sodium phosphate buffer solution (NaH) pH =7.4 2 PO 4 、Na 2 HPO 4 ) sEH enzyme, BSA, DMSO, a PHOME substrate, a positive control AR-9281 and a series of test compounds.
Information on sEH enzyme: the concentration was 2.74mg/mL for 50 μ g, and the volume was 18.2 μ L (TBS, pH =7.4, 20% ethylene glycol).
Dilution of sEH enzyme: mu.L of sEH enzyme was taken and 546. Mu.L of sodium phosphate buffer solution was added to give a 10. Mu.g/mL solution of sEH enzyme (548. Mu.L total) which was diluted to 1. Mu.g/mL with sodium phosphate buffer (containing 0.1 mg/mLBA) before use (in an ice box).
Preparation of a PHOME substrate: to 0.79mg of PHOME was added 106. Mu.L DMSO to obtain a 20mM solution of PHOME, which was diluted to 1/3mM (ready for use) with sodium phosphate buffer before use.
The experimental steps are as follows:
1. adding 74 mu L of pH =7.4 sodium phosphate buffer to each well of a 96-well plate;
2. a sample to be tested: mu.L (substrate group, substrate + enzyme group substituted with DMSO, positive control group added with AR-9281);
3. gradient dilution is carried out for 8 concentrations, wherein the concentrations are respectively 5000nM, 2500nM, 1250nM, 625nM, 312.5nM, 156.25nM, 78125nM and 39.0625nM, and nM is nmol/L;
4. s-EH:10 μ L (substrate set replaced with sodium phosphate buffer);
5. PHOME substrate: 15 mu L of the solution;
6. incubating at 37 ℃ for 10min;
7. fluorescence signal data (excitation wavelength 330nm, emission wavelength 465 nm) are detected by a microplate reader;
8. data are processed (the mean value of three complex wells is the fluorescence value of the compound to be tested), and the inhibition rate = [ (S-S1)/S]*100 (S: fluorescence of substrate + enzyme group; S1: fluorescence of test Compound), IC was calculated using GraphPadprism 6 50 The value is obtained.
Remarking: each sample is provided with three compound holes; PHOME final concentration c [ final ] =50 μ M; final enzyme concentration c [ final ] =100ng/mL, wherein μ M is μmol/L.
The inhibitory activities of the compounds I-1 to I-31 on human-derived soluble epoxyhydrolase (HsEH) and murine-derived soluble epoxyhydrolase (MsEH) are shown in Table 1:
TABLE 1 inhibitory Activity of Compounds I-1 to I-31 against human soluble epoxy hydrolase (HsEH) and murine soluble epoxy hydrolase (MsEH)
Figure BDA0002475795990000291
Figure BDA0002475795990000301
As can be seen from Table 1, the IC50 values of the compounds I-1 to I-31 prepared by the invention on HsEH and MsEH are between 0.4nM and 100 MuM, and the compounds have better inhibition effects, wherein the inhibition effects of the compounds I-13, I-14, I-15, I-22, I-23 and I-24 on HsEH and MsEH are better than that of the positive control AR-9281; the inhibition activity of the compounds I-13 and I-22 on HsEH and MsEH is 35 times that of the positive control AR-9281, and the compounds show very good development prospect.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.

Claims (2)

1. A sEH inhibitor characterized in that the sEH inhibitor is N- (((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) -4-oxo-4- (piperidin-1-yl) butanamide, N 1 -cyclohexyl-N 4 - ((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) succinimide, N 1 - (((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) -N 4 -isobutylsuccinimide, (Z) -N- (((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) -4-oxo-4- (piperidin-1-yl) but-2-enamide, N 1 -cyclohexyl-N 4 - ((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) fumaramide, N 1 - ((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) -N 4 Isobutyl fumaroyl, N- (((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) -5-oxo-5- (piperidin-1-yl) pentanamide, N 1 -cyclohexyl-N 5 - (((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) glutaramide, N 1 - ((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) -N 5 Isobutyl glutaramide, N- (((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) -4- (piperidine-1-carbonyl) benzamide, N 1 -cyclohexyl-N 4 - ((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) terephthalamide, N 1 - ((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) -N 4 -isobutylterephthalamide, 1- ((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) -3- (4- (piperidine-1-carbonyl) phenyl) urea, N-cyclohexyl-4- (3- (((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) ureido) benzamide, 4- (3- ((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) ureido) benzamide) -N-isobutylbenzamide, N 1 - ((5s, 7s) -5-hydroxyadamantan-2-yl) -N 5 Isobutylglutaramide, 1- ((5s, 7s) -5-hydroxyadamantan-2-yl) -3- (4- (piperidine-1-carbonyl) phenyl) urea, N-cyclohexyl-4- (3- (((5s, 7s) -5-hydroxyadamantan-2-yl) ureido) benzamide, 4- (3- ((5s, 7s) -5-hydroxyadamantan-2-yl) ureido) -N-isobutylbenzamide, 1- (((1r, 3s,5R, 7S) -3-hydroxyadamantan-1-yl) -3- (4- (piperidine-1-carbonyl) phenyl) urea, N-cyclohexyl-4- (3- (((1r, 3s,5R, 7S) -3-hydroxyadamantan-1-yl) ureido) benzamide or 4- (3- ((r, 1s, 5R, 7S) -3-hydroxyadamantan-1-yl) ureido) -N-isobutylbenzamide.
2. Use of the sEH inhibitor of claim 1 in the preparation of a medicament for treating a soluble epoxide hydrolase mediated disease.
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