Phenethyl imidazole derivative and application thereof
阅读说明：本技术 苯乙基咪唑类衍生物及其用途 (Phenethyl imidazole derivative and application thereof ) 是由 陈卫东 赵世振 王艳东 叶文凌 聂小博 周云 李新萍 于 2020-07-14 设计创作，主要内容包括：本发明属于医药技术领域,提供了如通式(Ι)新型苯基咪唑酰胺类衍生物及其几何异构体或其药学上可接受的盐、水合物、溶剂化物、前药和它们的制备方法。本发明的化合物能够激活TGR5活性,能够用于治疗或预防与TGR5活性调节有关的疾病。<Image he="365" wi="486" file="DDA0002582608410000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention belongs to the technical field of medicines, and provides a novel phenylimidazole amide derivative shown as a general formula (I), a geometric isomer thereof or pharmaceutically acceptable salts, hydrates, solvates and prodrugs thereof, and a preparation method thereof. The compounds of the invention are capable of activating TGR5Can be used for the treatment or prevention of diseases associated with modulation of TGR5 activity.)
1. A phenylimidazole derivative shown in a general formula (I), a geometric isomer thereof or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, which is characterized in that the general formula is as follows:
wherein the content of the first and second substances,
x is selected from H, (C)1-C6) An alkyl group;
R1selected from 1-3 hydrogen, hydroxyl, halogen, nitro,Amino, cyano, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkylthio, optionally substituted by hydroxy, amino or halogen (C)1-C6) Alkyl or (C)1-C6) Alkoxy or (C)1-C6) Alkylthio, mono-or di (C)1-C6Alkyl) substituted amino, (C)1-C6) Alkylamido, free, salified, esterified and amidated carboxyl, (C)1-C6) Alkylsulfinyl (C)1-C6) Alkylsulfonyl group, (C)1-C6) Alkanoyl, carbamoyl, mono-or di (C)1-C6Alkyl) substituted carbamoyl, (C)1-C3) An alkylenedioxy group;
the moiety of A ring is selected from
R2Selected from 1-3 hydrogen, hydroxyl, halogen, nitro, amino, cyano and (C)1-C6) Alkyl, (C)1-C6) Alkoxy group, (C)1-C6) An alkylthio group.
2. A phenylimidazolamide derivative of the general formula (I) as claimed in claim 1, and geometric isomers thereof or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, wherein
X is selected from H, CH3；
R1Selected from 1-3 hydrogen, hydroxyl, halogen, nitro, amino, cyano and (C)1-C6) Alkyl, (C)1-C6) An alkoxy group;
the moiety of A ring is selected from
R2Selected from 1-3 hydrogen, hydroxyl, halogen, nitro, amino, cyano and (C)1-C6) Alkyl, (C)1-C6) An alkoxy group.
3. The phenylimidazolamide derivatives of the general formula (I) according to claim 1, their geometric isomers or their pharmaceutically acceptable salts, hydrates, solvates or prodrugs,
wherein:
x is selected from H, CH3；
R1Selected from 1-3 hydrogen, halogen, amino, (C)1-C6) Alkyl, (C)1-C6) An alkoxy group;
the moiety of A ring is selected from
R2Selected from 1-3 halogens, (C)1-C6) Alkyl, (C)1-C6) An alkoxy group.
4. A compound of formula (I) as claimed in any one of claims 1 to 3, and geometric isomers thereof or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, characterized in that it is selected from:
(R) - (1- (1-phenylethyl) -1H-imidazol-5-yl) (4-phenylpiperazin-1-yl) methanone
(R) - (4- (2-fluorophenethyl) piperazin-1-yl) (1- (1-phenylethyl) -1H-imidazol-5-yl) methanone
(R) - (4- (4-methoxyphenethyl) piperazin-1-yl) (1- (1-phenylethyl) -1H-imidazol-5-yl) methanone
(R) - (4- (2-methoxyphenethyl) piperazin-1-yl) (1- (1-phenylethyl) -1H-imidazol-5-yl) methanone
(R) - (4-cyclopropyl-3, 4-dihydroquinoxalin-1 (2H) -yl) (1- (1-phenylethyl) -1H-imidazol-5-yl) methanone
(R) - (3, 4-dihydroquinolin-1 (2H) -yl) (1- (1-phenylethyl) -1H-imidazol-5-yl) methanone
(R) - (2, 3-dihydro-4H-benzo [ b ] [1,4] oxazin-4-yl) (1- (1-phenylethyl) -1H-imidazol-5-yl) methanone
(1-benzyl-1H-imidazol-5-yl) (4-cyclopropyl-3, 4-dihydroquinoxalin-1 (2H) -yl) methanone
(4-cyclopropyl-3, 4-dihydroquinoxalin-1 (2H) -yl) (1- (4-fluorobenzyl) -1H-imidazol-5-yl) methanone
(4-cyclopropyl-3, 4-dihydroquinoxalin-1 (2H) -yl) (1- (2-chlorobenzyl) -1H-imidazol-5-yl) methanone
(4-cyclopropyl-3, 4-dihydroquinoxalin-1 (2H) -yl) (1- (2, 4-dichlorobenzyl) -1H-imidazol-5-yl) methanone
(4-cyclopropyl-3, 4-dihydroquinoxalin-1 (2H) -yl) (1- (2, 5-dichlorobenzyl) -1H-imidazol-5-yl) methanone
(4-cyclopropyl-3, 4-dihydroquinoxalin-1 (2H) -yl) (1- (2, 4-difluorobenzyl) -1H-imidazol-5-yl) methanone.
5. Use of phenylimidazole derivatives of general formula (I) according to any of claims 1 to 4 for the treatment of diseases and conditions in which TGR5 is involved in a biopathological process.
6. The treatment of diseases and conditions of the biopathological process in which TGR5 is involved, according to claim 5, characterized by, in particular, diabetes, hyperglycemia, obesity, hypercholesterolemia, lipid disorders or fatty liver.
Technical Field
The invention belongs to the technical field of medicaments, and particularly relates to novel phenylimidazole amide derivatives, pharmaceutically acceptable salts, hydrates, solvates or prodrugs of the compounds, a preparation method of the derivatives and medicinal application of the derivatives as medicaments for treating diseases and symptoms of biological pathological processes involving TGR 5.
Background
The TGR5 receptor is a bile acid membrane receptor and was first discovered in 2002 by Maruyama and Kawamata to consist of 330 amino acids, contain 7 transmembrane domains, and belong to the GPCR family. TGR5 is distributed mainly in the gallbladder, intestinal tract, adipose tissue, muscle tissue and gallbladder. TGR5 plays an important regulatory role in various physiological processes, such as energy metabolism, immune inflammatory response, hepatobiliary system function, gastrointestinal system function, etc.
The TGR5 receptor is most fully studied in the aspect of regulation of energy metabolism at present, and the stimulation of the TGR5 receptor in the intestinal tract can promote the L cells in the intestinal tract to secrete GLP-1, GLP-2 and PYY (peptide tyrosine-tyrosine which is secreted by ileum and colon cells and can promote satiety). GLP-1 can promote insulin secretion dependent on blood glucose level, inhibit glycogenolysis, suppress appetite, slow gastrointestinal tract emptying and increase glucose uptake in peripheral tissues. Elevated PYY levels can increase satiety and decrease food intake. In addition, TGR5 receptor regulates the function of islet alpha and beta cells, thereby achieving the effect of reducing blood sugar. Activation of the TGR5 receptor on islet beta cells may directly promote insulin secretion, while activation of the TGR5 receptor on islet alpha cells indirectly promotes insulin secretion by promoting GLP-1 secretion through the Epac pathway. The research shows that the TGR5 agonist has potential therapeutic value in the aspect of treating metabolic diseases such as diabetes, obesity and the like.
TGR5 agonists currently under investigation include primarily steroidal and non-steroidal compounds. In the steroid TGR5 agonist, INT-777 is a selective TGR5 agonist, and can increase energy metabolism, reduce weight increase, reduce liver fat content, and has beneficial therapeutic effect on hyperglycemia and fatty liver. However, steroid agonists have the disadvantages of poor selectivity, strong toxic and side effects and the like. The non-steroidal TGR5 agonists in the research mainly included: disubstituted isoxazolecarboxamides and aminomethyl quinolines.
The inventor designs and synthesizes a series of novel phenylimidazole derivatives on the basis of the reference. The compound has stronger TGR5 agonistic activity through in vitro activity tests, and can effectively reduce the blood sugar level in a mouse test.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a novel phenylimidazole amide derivative, a preparation method of the compound and application of the compound.
In order to achieve the purpose, the invention adopts the technical scheme that: the invention provides a novel phenylimidazole amide derivative shown in a general formula (I), and a geometric isomer thereof or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof;
wherein X is selected from H and (C)1-C6) An alkyl group;
R1selected from 1-3 hydroxyl, halogen, nitro, amino, cyano and (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkylthio, optionally substituted by hydroxy, amino or halogen (C)1-C6) Alkyl or (C)1-C6) Alkoxy or (C)1-C6) Alkylthio, mono-or di (C)1-C6Alkyl) substituted amino, (C)1-C6) Alkylamido, free, salified, esterified and amidated carboxyl, (C)1-C6) Alkylsulfinyl (C)1-C6) Alkylsulfonyl group, (C)1-C6) Alkanoyl, carbamoyl, mono-or di (C)1-C6Alkyl) substituted carbamoyl, (C)1-C3) An alkylenedioxy group;
the moiety of A ring is selected from
R2Selected from 1-3 hydroxyl, halogen, nitro, amino, cyano and (C)1-C6) Alkyl, (C)1-C6) Alkoxy group, (C)1-C6) An alkylthio group.
The invention preferably relates to novel phenylimidazole amide derivatives shown in a general formula (I), geometrical isomers thereof or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, wherein:
x is selected from H, CH3；
R1Selected from 1-3 hydroxyl, halogen, nitro, amino, cyano and (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)1-C6) An alkoxy group;
the moiety of A ring is selected from
R2Selected from 1-3 hydroxyl, halogen, nitro, amino, (C)1-C6) Alkyl, (C)1-C6) An alkoxy group.
The compounds represented by the general formula (I) of the present invention, and geometric isomers thereof or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, are preferably the following compounds, but these compounds are not meant to limit the present invention in any way:
(R) - (1- (1-phenylethyl) -1H-imidazol-5-yl) (4-phenylpiperazin-1-yl) methanone
(R) - (4- (2-fluorophenethyl) piperazin-1-yl) (1- (1-phenylethyl) -1H-imidazol-5-yl) methanone
(R) - (4- (4-methoxyphenethyl) piperazin-1-yl) (1- (1-phenylethyl) -1H-imidazol-5-yl) methanone
(R) - (4- (2-methoxyphenethyl) piperazin-1-yl) (1- (1-phenylethyl) -1H-imidazol-5-yl) methanone
(R) - (4-cyclopropyl-3, 4-dihydroquinoxalin-1 (2H) -yl) (1- (1-phenylethyl) -1H-imidazol-5-yl) methanone
(R) - (3, 4-dihydroquinolin-1 (2H) -yl) (1- (1-phenylethyl) -1H-imidazol-5-yl) methanone
(R) - (2, 3-dihydro-4H-benzo [ b ] [1,4] oxazin-4-yl) (1- (1-phenylethyl) -1H-imidazol-5-yl) methanone
(1-benzyl-1H-imidazol-5-yl) (4-cyclopropyl-3, 4-dihydroquinoxalin-1 (2H) -yl) methanone
(4-cyclopropyl-3, 4-dihydroquinoxalin-1 (2H) -yl) (1- (4-fluorobenzyl) -1H-imidazol-5-yl) methanone
(4-cyclopropyl-3, 4-dihydroquinoxalin-1 (2H) -yl) (1- (2-chlorobenzyl) -1H-imidazol-5-yl) methanone
(4-cyclopropyl-3, 4-dihydroquinoxalin-1 (2H) -yl) (1- (2, 4-dichlorobenzyl) -1H-imidazol-5-yl) methanone
(4-cyclopropyl-3, 4-dihydroquinoxalin-1 (2H) -yl) (1- (2, 5-dichlorobenzyl) -1H-imidazol-5-yl) methanone
(4-cyclopropyl-3, 4-dihydroquinoxalin-1 (2H) -yl) (1- (2, 4-difluorobenzyl) -1H-imidazol-5-yl) methanone
Furthermore, some of the compounds of formula (I) of the present invention have basic groups and can form pharmaceutically acceptable salts with acids according to conventional methods in the art. Pharmaceutically acceptable addition salts include inorganic and organic acid addition salts, with the following acids being particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, and the like. Most preferred is hydrochloric acid.
In addition, the present invention also includes prodrugs of the derivatives of the present invention. Prodrugs of the derivatives of the invention are derivatives of formula (I) which may themselves have weak or even no activity, but which, upon administration, are converted under physiological conditions (e.g. by metabolism, solvolysis or otherwise) to the corresponding biologically active form.
The compounds of formula (I) may be in unsolvated form as well as solvated forms containing pharmaceutically acceptable solvents such as water, ethanol, and the like. The compounds of formula (I) may contain asymmetric or chiral centers and may therefore exist in different stereoisomeric forms. All stereoisomeric forms of the present invention, including but not limited to diastereomers, enantiomers, and atropisomers, and mixtures thereof (e.g., racemic mixtures), are included within the scope of the present invention.
The compounds of formula (I) may exist in different tautomeric forms, all of which are included within the scope of the invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are mutually converted via a low energy barrier.
"halogen" in the present invention means fluoro, chloro, bromo or iodo; "alkyl" refers to straight or branched chain alkyl; pyrrolidinyl, morpholinyl, piperidinyl, tetrahydropyrazolidinyl, tetrahydroimidazolidinyl, thiazolidinyl, and the like.
The invention can contain the derivatives of the general formula (I) and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof as active ingredients, and the derivatives, the pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof are mixed with pharmaceutically acceptable carriers or excipients to prepare a composition and prepare a clinically acceptable dosage form, wherein the pharmaceutically acceptable excipients refer to any diluents, auxiliary agents and/or carriers which can be used in the pharmaceutical field. The derivatives of the present invention may be used in combination with other active ingredients as long as they do not produce other adverse effects, such as allergic reactions.
The pharmaceutical composition of the present invention can be formulated into several dosage forms containing some excipients commonly used in the pharmaceutical field. The above-mentioned several dosage forms can adopt the dosage forms of injection, tablet, capsule, aerosol, suppository, membrane, dripping pill, external liniment and ointment, etc.
Carriers for the pharmaceutical compositions of the present invention are of the usual type available in the pharmaceutical art, including: binder, lubricant, disintegrating agent, cosolvent, diluent, stabilizer, suspending agent, pigment-free, correctant, antiseptic, solubilizer, matrix, etc. Pharmaceutical formulations may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically), and if certain drugs are unstable under gastric conditions, they may be formulated as enteric coated tablets.
The derivatives of formula (I) which may be comprised by the present invention may be synthesized by methods well known in the art including chemistry, in particular in accordance with the teachings of the present invention.
The starting materials are generally available from commercial sources such as the reagent companies avastin, dary, etc. or are prepared using methods well known to those skilled in the art.
The room temperature in the present invention means an ambient temperature of 10 to 30 ℃.
The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and their methods of preparation. It should be understood that the scope of the following examples and preparations are not intended to limit the scope of the invention in any way. The compounds of formula I according to the present invention can be prepared according to the methods of schemes 1-2.
Drawings
FIG. 1 OGTT test in C57L/6J mice after a single administration.
In specific examples, the compounds of examples 1-7 were synthesized according to the synthetic route of route 1, starting with etomidate 1, first hydrolyzed under alkaline conditions to obtain intermediate 2, which was then condensed with various substituted N-phenylpiperazines or substituted tetrahydroquinoxalines in the condensing agent HATU to obtain the compounds of examples 1-7.
Scheme 1 reagents and conditions (a) NaOH, MeOH/H2O,r.t.；(b)HATU,DIEA,DMF,r.t..