CN107162982B - Imidazole compounds with anticancer activity and derivatives thereof - Google Patents

Imidazole compounds with anticancer activity and derivatives thereof Download PDF

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CN107162982B
CN107162982B CN201710468224.9A CN201710468224A CN107162982B CN 107162982 B CN107162982 B CN 107162982B CN 201710468224 A CN201710468224 A CN 201710468224A CN 107162982 B CN107162982 B CN 107162982B
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cancer
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imidazole
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CN107162982A (en
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曹华
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Huaji Pharmaceutical Technology Beijing Co ltd
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Guangdong Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

The invention relates to imidazole compounds with anticancer activity and derivatives thereof. It is represented by the following formula:

Description

Imidazole compounds with anticancer activity and derivatives thereof
Technical Field
The invention relates to an imidazole compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof or a solvate thereof. The invention further relates to pharmaceutical compositions containing at least one compound of the invention for use in the treatment of cancer.
Background
Cancer is one of the important diseases that currently seriously threaten human health, and the treatment and prevention thereof draws extensive attention. The current treatment methods include surgical excision, radiotherapy, chemical drug therapy and the like, but mainly include chemical drug therapy. The current clinical chemical drugs for treating cancer are in a wide variety, such as platinum, nitrogen mustard, triazole and the like, but most drugs are limited in application due to high toxicity, multiple adverse reactions and low bioavailability. Therefore, the search for highly effective and low toxic anticancer drugs has become one of the key research subjects in the field of pharmaceutical chemistry at present.
Imidazole ring is an important group for generating biological activity and playing physiological role of histamine and histidine in organisms. The imidazole ring is a five-membered aromatic nitrogen heterocycle containing 2 nitrogen atoms in the structure, and is easy to generate various non-covalent bond interactions, such as hydrogen bond, coordination with metal ions, pi 2 pi interaction and the like. Imidazole derivatives constructed by the imidazole ring with the special structure have larger development potential, such as being used for molecular recognition as an artificial receptor, being used for biomimetic catalysis as an artificial enzyme, and having wide biological activity as a medicament, such as histamine receptor retarder, proton pump inhibitor, antivirus, anticancer and the like. Especially as anticancer drugs, show a wide application prospect, and the research thereof is concerned and increasingly active in recent years. Many important achievements have been made in this field, among which several imidazole compounds have been used clinically as anticancer drugs, such as sodium glycinediazole, fadrozole, dacarbazine (dacarba-zine), temozolomide, etc.
In view of the potential application of imidazole anticancer drugs in cancer treatment, and the authors do not report the research and development profile of imidazole derivatives in the whole anticancer drug field in the literature at home and abroad, and in combination with the research work in the laboratory, the latest research and development progress of imidazole compounds as anticancer drugs in the aspects of radiosensitizers, farnesyl transferase inhibitors, cytochrome P450 inhibitors, angiogenesis inhibitors, topoisomerase inhibitors, cyclin-dependent protein kinase inhibitors, tumor resistance reversal agents and the like is reviewed here.
The invention relates to a novel imidazole compound which can effectively inhibit various cancers or tumors.
Disclosure of Invention
The invention provides an imidazole compound with anticancer activity and a derivative thereof.
The invention aims to provide the compound for treating various cancers or tumors, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof.
The invention also provides processes and intermediates for preparing the compounds of the invention or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.
The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one compound of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof.
The present invention also provides a method of treating a tumor or cancer comprising administering to a host in need of treatment a therapeutically effective amount of at least one compound of the present invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof.
Preferred embodiments are the treatment of various tumors or cancers.
The invention also provides said compounds for use in therapy or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, and solvates thereof
An acceptable salt, solvate or prodrug thereof.
The invention also provides the compound or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof, which is used for preparing a medicament for treating cancer.
These and other features of the present invention will be described in further detail.
The invention provides a compound of formula (I),
or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof, as shown below:
Figure BSA0000146317310000021
wherein
R 1Independently selected from substituted or unsubstituted C 1-6Alkyl, substituted or unsubstituted C 1-6Haloalkyl, substituted or unsubstituted C 2-6Alkenyl, substituted or unsubstituted C 2-6Alkynyl, substituted or unsubstituted C 3-10Cycloalkyl, substituted or unsubstituted C 6-10Aryl radical containing 1-4 substituents selected fromN, O and a heteroatom in S, or a substituted or unsubstituted 5-10 membered heteroaryl group containing 1-4 heteroatoms selected from N, O and S;
R 2independently selected from substituted or unsubstituted C 1-6Alkyl, substituted or unsubstituted C 1-6Haloalkyl, substituted or unsubstituted C 2-6Alkenyl, substituted or unsubstituted C 2-6Alkynyl, substituted or unsubstituted C 3-10Cycloalkyl, substituted or unsubstituted C 6-10Aryl, a substituted or unsubstituted 5-10 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S, or a substituted or unsubstituted 5-10 membered heteroaryl group containing 1-4 heteroatoms selected from N, O and S;
R 3independently selected from substituted or unsubstituted C 1-6Alkyl, substituted or unsubstituted C 1-6Haloalkyl, substituted or unsubstituted C 2-6Alkenyl, substituted or unsubstituted C 2-6Alkynyl, substituted or unsubstituted C 3-10Cycloalkyl, substituted or unsubstituted C 6-10Aryl, a substituted or unsubstituted 5-10 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S, or a substituted or unsubstituted 5-10 membered heteroaryl group containing 1-4 heteroatoms selected from N, O and S;
r is independently selected from substituted or unsubstituted C 1-6Alkyl, substituted or unsubstituted C 1-6Haloalkyl, substituted or unsubstituted C 2-6Alkenyl, substituted or unsubstituted C 2-6Alkynyl, substituted or unsubstituted C 3-10Cycloalkyl, substituted or unsubstituted C 6-10Aryl, a substituted or unsubstituted 5-to 10-membered heterocycle containing 1 to 4 heteroatoms selected from N, O and S, or a substituted or unsubstituted 5-to 10-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O and S.
Preferably, when substituted as described herein, it means that the corresponding group is substituted by halogen, NH 2、OH、C 1-6Alkyl radical, C 2-6Alkenyl radical, C 2-6Alkynyl, C 3-10Cycloalkyl radical, C 6-10Aryl, 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S.
Preferably, the aryl group is selected from phenyl, naphthyl, anthryl or phenanthryl.
Preferably, the heteroaryl group is selected from the group consisting of indolinyl, benzothiazolyl, pyrazolopyridinyl, benzisothiazolyl, triazolopyridinyl, imidazopyridinyl, benzoxazolyl, triazolopyridinyl, imidazopyridinyl, pyridopyrazinyl, quinazolinyl, pyridopyrazinyl, benzooxadiazolyl, benzothiadiazolyl, benzimidazolyl.
More preferably, the compounds of the invention are selected from the following specific compounds:
Figure BSA0000146317310000022
Figure BSA0000146317310000031
the invention also provides a preparation method of the compound, which comprises the step of taking N-substituted amidine and substituted alkynal as raw materials to react in an oil bath kettle to prepare the compound. It will be appreciated by those skilled in the art that in preparing the starting compounds, the starting compounds may be selected as the case may be.
The invention provides a composition which is characterized by comprising a compound shown as I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof or a solvate thereof, and a pharmaceutically acceptable auxiliary agent, carrier or diluent.
Preferably, the composition can be prepared into various dosage forms, and the dosage forms are selected from plain tablets, film-coated tablets, sugar-coated tablets, enteric-coated tablets, dispersible tablets, capsules, granules, oral solutions or oral suspensions.
The compound shown in the invention, or a stereoisomer thereof, or a pharmaceutically acceptable salt or a solvate thereof is used for preparing tumors or cancers, wherein the tumors or cancers are gastric cancer, cervical adenocarcinoma, colon cancer, lung cancer, liver cancer, glioma, esophageal cancer, intestinal cancer, nasopharyngeal cancer, breast cancer, lymph cancer, kidney cancer, pancreatic cancer, bladder cancer, ovarian cancer, uterine cancer, bone cancer, gallbladder cancer, lip cancer, melanoma, tongue cancer, laryngeal cancer, leukemia, prostate cancer, brain tumor, squamous cell cancer, skin cancer, hemangioma, lipoma, cervical cancer and thyroid cancer.
The invention also provides processes and intermediates for preparing the compounds of the invention, stereoisomers, tautomers, pharmaceutically acceptable salts, solvates or prodrugs thereof.
The present invention also provides a method of treating tumors or cancers (or the use of a compound of the present invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof, for the manufacture of a medicament for the treatment of such diseases), comprising administering to a host in need of treatment a therapeutically effective amount of at least one compound of the present invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.
The invention also provides a method of treating a disease (or the use of a compound of the invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof, for the manufacture of a medicament for the treatment of such a disease) comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I, wherein the disease is gastric cancer, cervical adenocarcinoma, colon cancer, lung cancer, liver cancer, glioma, esophageal cancer, intestinal cancer, nasopharyngeal cancer, breast cancer, lymphatic cancer, kidney cancer, pancreatic cancer, bladder cancer, ovarian cancer, uterine cancer, bone cancer, gall bladder cancer, lip cancer, melanoma, tongue cancer, laryngeal cancer, leukemia, prostate cancer, brain cancer, squamous cell cancer, skin cancer, hemangioma, lipoma, cervical cancer and thyroid cancer.
The invention also provides a method of treating a disease comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, in combination with other therapeutic agents.
The invention also provides the compounds, or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, for use in therapy.
In another embodiment, the compound of formula I is selected from the exemplified compounds or combinations of the exemplified compounds or other embodiments herein.
In another embodiment, the invention is directed to pharmaceutical compositions comprising a compound of formula (I) and one or more active ingredients.
The term "alkyl" as used herein is intended to include both branched and straight chain saturated hydrocarbon radicals having the specified number of carbon atoms. E.g. "C 1-10Alkyl "(or alkylene) groups are intended to be C1, C2, C3, C4, C5, C6, C7, C8, C9 and C10 alkyl groups. In addition, for example "C 1-6Alkyl "denotes an alkyl group having 1 to 6 carbon atoms. Alkyl groups may be unsubstituted or substituted such that one or more of its hydrogen atoms are replaced with another chemical group. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.
"alkenyl" is a hydrocarbon group that includes both straight and branched chain structures and has one or more carbon-carbon double bonds that occur at any stable point in the chain. E.g. "C 2-6Alkenyl "(or alkenylene) is intended to include C2, C3, C4, C5, and C6 alkenyl. Examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like.
"alkynyl" is intended to include both straight and branched chain hydrocarbons having one or more carbon-carbon triple bonds at any stable point in the chain. E.g. "C 2-6Alkynyl "(or alkynylene) is intended to include C2, C3, C4, C5, and C6 alkynyl; such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.
When reference is made to substituted alkenyl, alkynyl, alkylene, alkenylene or alkynylene, these groups are substituted with one to three alkyl substituents as described above.
The term "substituted" as used herein means that any one or more hydrogen atoms on the designated atom or group is replaced with the designated group of choice, provided that the general valence of the designated atom is not exceeded. When the substituent is oxygen or a ketone (i.e., ═ O), then 2 hydrogen atoms on the atom are substituted. The keto substituent is absent from the aromatic fragment. If not otherwise stated, substituents are named to the central structure. For example, it is understood that when (cycloalkyl) alkyl is a possible substituent, the point of attachment of the substituent to the central structure is in the alkyl moiety. As used herein, a cyclic double bond is a double bond formed between two adjacent ring atoms (e.g., C ═ C, C ═ N or N ═ N).
Combinations of substituents and or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure implies that the compound is sufficiently stable to be isolated in useful purity from the reaction mixture and subsequently formulated to form an effective therapeutic agent. Preferably, the compounds described so far do not contain N-halogen, S (O) 2H or S (O) H group.
The term "cycloalkyl" refers to cycloalkyl groups, including mono-, bi-or polycyclic ring systems. C3-7 cycloalkyl is intended to include C3, C4, C5, C6 and C7 cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. As used herein, "carbocycle" or "carbocycle residue" refers to any stable 3, 4, 5, 6 or 7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12 or 13-membered bi-or tricyclic ring which may be saturated, partially unsaturated, unsaturated or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, pentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadiene, [3.3.0] bicyclooctane, [4.3.0] bicyclononane, [4.4.0] bicyclodecane, [2.2.2] bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As mentioned above, bridged rings are also included in the definition of carbocyclic rings (e.g., [2.2.2] bicyclooctane). Preferred carbocycles, if not otherwise stated, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and phenyl. When the term "carbocycle" is used, it is intended to include "aryl". A bridged ring occurs when one or more carbon atoms connects two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It is pointed out that the bridge always converts a single ring into a double ring. When the rings are bridged, substituents of the rings are also present on the bridge.
The term "aryl" refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl and naphthyl, each of which may be substituted.
The term "halogen" or "halogen" refers to chlorine, bromine, fluorine and iodine.
The term "haloalkyl" refers to a substituted alkyl having one or more halo substituents. For example, "haloalkyl" includes mono-, di-and trifluoromethyl.
The term "heteroaryl" refers to substituted and unsubstituted aromatic 5 or 6 membered monocyclic groups, 9-or 10-membered bicyclic groups, and 11 to 14 membered tricyclic groups having at least one heteroatom (O, S or N) in at least one ring, said heteroatom containing ring preferably having 1, 2 or 3 heteroatoms selected from O, S and N. The heteroatom-containing heteroaryl groups can contain one or two oxygen or sulfur atoms per ring and/or from 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less and each ring has at least one carbon atom. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. Bicyclic or tricyclic heteroaryl groups must include at least one fully aromatic ring, and the other fused rings may be aromatic or non-aromatic. The heteroaryl group may be attached at any available nitrogen or carbon atom of any ring. If the other ring is cycloalkyl or heterocyclic, it is additionally optionally substituted with ═ O (oxygen), as valency permits.
Exemplary monocyclic heteroaryls include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and the like.
Exemplary bicyclic heteroaryls include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, fluoropyridinyl, dihydroisoindolyl, tetrahydroquinolinyl, and the like.
The compounds of the invention are understood to include both the free form and salts thereof, unless otherwise indicated. The term "salt" means an acid and/or base salt formed from an inorganic and/or organic acid and a base. In addition, the term "salt" may include zwitterions (internal salts), such as when the compound of formula I contains a basic moiety, such as an amine or pyridine or imidazole ring, and an acidic moiety, such as a carboxylic acid. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, such as acceptable metal and amine salts, wherein the cation does not contribute significantly to the toxicity or biological activity of the salt. However, other salts may be useful, such as separation or purification steps in the preparation process, and are therefore included within the scope of the present invention. Salts of the compounds of formula I may be formed, for example, by combining a compound of formula I with an amount of acid or base, for example, in equal amounts, in a vehicle, for example, in which the salt precipitates or in which it is present in an aqueous vehicle, and then lyophilizing.
Exemplary acid addition salts include acetate (e.g., formed with acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride (formed with hydrochloric acid), hydrobromide (formed with hydrobromic acid), hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate (formed with maleic acid), methanesulfonate (formed with methanesulfonic acid), 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pectate, persulfate, 3-phenylpropionate, salts of benzoic acid, salts of, Phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, tosylates such as tosylate, undecanoate, and the like.
Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, barium, zinc and aluminum salts, salts with organic bases (e.g., organic amines) such as trialkylamines such as triethylamine, procaine, dibenzylamine, N-benzyl- β -phenylethylamine, 1-diphenylmethylolmethylamine, N' -dibenzylethylenediamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamine or similar pharmaceutically acceptable amines and salts with amino acids such as arginine, lysine and the like.
The phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without additional toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.
As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified with an acid or its basic salt. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic groups such as amines; and acid groups such as bases or organic salts of carboxylic acids. Pharmaceutically acceptable salts include the conventional non-toxic salts or parent compounds forming quaternary ammonium salts, e.g. from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid; and salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-ethoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic acid and the like.
The pharmaceutically acceptable salts of the present invention may be synthesized from parent compounds containing either a basic or acidic moiety by conventional chemical methods. Generally, these salts can be prepared from the free acid or base forms of these compounds with a stoichiometric ratio of the appropriate base or acid in water or an organic solvent, or a mixture of the two; generally, nonaqueous vehicles such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
All stereoisomers of the compounds of the invention are contemplated, both in admixture or in pure or substantially pure form. Stereoisomers may include compounds that are optical isomers substituted by one or more chiral atoms, as well as compounds that are optical isomers by restricting the rotation of one or more bonds (atropisomers). The definition of the compounds of the present invention includes all possible stereoisomers and mixtures thereof. It includes especially the racemic form and the isolated optical isomers which have particular activity. Resolution of racemic forms by physical means, for example fractional crystallisation, separation or crystallisation of stereoisomeric derivatives or separation by chiral column chromatography. The individual optical isomers such as salts with optically active acids are obtained from the racemic salts by conventional methods and then crystallized.
Prodrugs and solvates of the compounds of the present invention are also contemplated. The term "prodrug" denotes a compound that undergoes a chemical reaction, either metabolically or chemically, upon administration to a receptor, to yield a compound of formula I, and/or a salt and/or solvate thereof. Any compound that is converted in vivo to provide a biologically active agent (i.e., a compound of formula I) is a prodrug within the scope and spirit of the invention. For example, compounds containing a carboxyl group may form physiologically hydrolyzable esters as prodrugs, which upon hydrolysis in vivo yield the compounds of formula I themselves. These prodrugs are preferably administered orally, since hydrolysis under many conditions occurs substantially under the influence of digestive enzymes. Parenteral administration can be used, the ester itself being active, in those instances hydrolysis occurs in the blood. The physiology of the Compounds of formula IExamples of the hydrolyzable esters include C 1-6Alkylbenzyl, 4-methoxybenzyl, indanyl, phthaloyl, methoxymethyl, C 1-6alkanoyloxy-C 1-6Alkyl radicals such as acetoxymethyl, pivaloyloxymethyl or propoxymethyl, C 1-6Alkoxy carbonyloxy-C 1-6Alkyl radicals, such as methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl, glycinyloxymethyl, phenylglycinyloxymethyl, (5-methyl-2-oxo-1, 3-dioxol-4-yl) -methyl and other well-known physiologically hydrolyzable esters of use, for example in the field of penicillin and cepalogensporin. These esters can be prepared by conventional techniques known in the art. Various forms of prodrugs are well known in the art.
"pharmaceutically acceptable carrier" refers generally to a carrier generally accepted in the art for delivering a biologically active agent to an animal, particularly a mammal. The pharmaceutically acceptable carrier is formulated according to a number of factors well known to those of ordinary skill in the art. These include without limitation the type and nature of the active agent being formulated; a subject to which a composition comprising the agent is administered; the route of administration of the composition; and directional therapy instructions. Pharmaceutically acceptable carriers include aqueous and non-aqueous liquid vehicles, and a variety of solid and semi-solid dosage forms. These carriers include many different components and additives in addition to the active agent, such additional components being included in the formulation for a variety of reasons, such as stability of the active agent, binder, etc., as is well known to those of ordinary skill in the art.
The compounds of formula I of the present invention may be administered in any suitable manner for treating a condition, depending on the site-specific treatment or the amount of drug delivered. Topical administration is generally preferred for systemic treatment of skin-related diseases, cancerous or pre-cancerous conditions, but other modes of delivery are contemplated. For example, orally administered compounds, such as in the form of tablets, capsules, granules, powders, or liquid formulations including syrups; topically such as in solution, suspension, gel or ointment; sublingual administration; the cheek floor; parenteral administration, e.g., by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion (e.g., sterile aqueous or nonaqueous solution or suspension); nasal such as by inhalation spray; topically such as in the form of a lotion or ointment; rectally, e.g., in suppository form; or liposomal. Dosage unit formulations containing non-toxic, pharmaceutically acceptable excipients or diluents may be administered. The compound may be administered in an immediate release or delayed release form. Immediate release or delayed release may be achieved with suitable pharmaceutical compositions, in the case of partial delayed release, using devices such as subcutaneous implants or osmotic pumps.
Exemplary compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose for delivery, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweetening or flavoring agents such as those known in the art; immediate release tablets may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art. The compounds of the present invention may also be delivered orally by sublingual and/or buccal administration, such as compression molding, compressed or lyophilized tablets. Exemplary compositions may include fast dissolving diluents such as mannitol, lactose, sucrose, and/or cyclodextrins. Included in these formulations may also be high molecular weight excipients such as cellulose
Figure BSA0000146317310000081
Or polyethylene glycol (PEG); excipients which aid mucosal adhesion such as hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), sodium carboxymethylcellulose (SCMC) and/or maleic anhydride copolymers (e.g. HPMC)
Figure BSA0000146317310000082
) (ii) a And release controlling agents such as polyacrylic acid copolymers (e.g. CARBOPOL)
Figure BSA0000146317310000083
). Lubricants, glidants, flavors, colorants and stabilizers may also be added to aid in preparation and use.
Exemplary compositions for administration by spraying or inhalation include solutions which may contain benzyl alcohol or other suitable preservatives, absorption promoters to enhance absorption and/or biological activity, and/or other soluble or dispersible agents such as those known in the art.
Exemplary compositions for parenteral administration include injection solutions or suspensions which may contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1, 3-butanediol, water, geline's solution, isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono-or diglycerides, and fatty acids, including oleic acid.
Exemplary compositions for rectal administration include suppositories which may contain, for example, suitable non-irritating excipients such as cocoa butter, synthetic glycerides or polyethylene glycols which are solid at ordinary temperatures but dissolve and/or dissolve in the gastrointestinal tract to release the drug.
A therapeutically effective amount of a compound of the present invention can be determined by one of ordinary skill in the art and includes exemplary dosages of from about 0.05 to 1000 mg/kg; 1-1000 mg/kg; 1-50 mg/kg; 5-250 mg/kg; 250-1000mg/kg, which can be administered in a single dose or in separate divided doses, e.g. from 1 to 4 times daily, in terms of the amount of active compound per kg of body weight per day. It will be understood that the specific dose level and frequency of dosage for a particular subject may be varied depending upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the race, age, body weight, general health, sex and diet of the subject, mode and time of administration, rate of excretion, drug combination and the severity of the particular disease. Preferred recipients for use in therapy include animals, most preferably mammalian races such as humans and poultry animals such as dogs, cats, horses and the like.
Examples
The invention is further illustrated by the following examples. It should be understood that the method described in the examples is only for illustrating the present invention and not for limiting the present invention, and that simple modifications of the preparation method of the present invention based on the concept of the present invention are within the scope of the claimed invention. All materials and solvents used in the examples were purchased from Sigma Biochemical and Organic Compounds for Research and diagnostic Reagents, unless otherwise specified.
Example 1: 5- (ethoxy (phenyl) methyl) -1, 2-diphenyl-1H-imidazole (yield 88%)
To a 25mL schlenk tube were added N-phenylbenzamidine (0.20mmol), AgOAc (2.5 mol%), TsOH (5 mol%), toluene (2mL), phenylpropylaldehyde (0.20mmol), ethanol (0.60mmol) successively, followed by N-sparge into the schlenk tube 2Stirring at 100 deg.C for 10 hr, detecting by TLC, cooling to room temperature, adding 10mL saturated saline solution into the reaction mixture, extracting with ethyl acetate (10mL × 3), mixing the organic layers, washing with saturated saline solution, and adding anhydrous MgSO 4Drying is carried out. The organic phase obtained is distilled under reduced pressure to remove most of the solvent, and the crude product is separated and purified by column chromatography. Structure of the product 1H NMR， 13C NMR, GC-MS, HRMS, IR and the like.
Brown solid, m.p.124-126 deg.C, 62.3mg. 1H NMR(400MHz，CDCl 3)δ7.45-7.30(m，12H)，7.22-7.17(m，3H)，6.80(s，1H)，5.12(s，1H)，3.37-3.29(m，1H)，3.13-3.05(m，1H)，1.08(t，J＝6.8Hz，3H). 13C NMR(100MHz，CDCl 3)δ148.4，139.0，137.3，135.5，130.5，129.0，128.8，128.5，128.3，128.2，128.1，127.9，127.2，75.1，64.4，15.1.ESI-MS m/z(％)354(100)[M+H] +；Anal.Calcd for C 24H 22N 2O C，81.33；H，6.26；N，7.90；Found：C，81.33；H，6.26；N，7.90.
The following compounds were prepared in analogy to the preparation of example 1, using only different starting materials.
Example 2: 5- (ethoxy (phenyl) methyl) -2-phenyl-1- (m-tolyl) -1H-imidazole (yield 75%)
Figure BSA0000146317310000091
Yellow solid, m.p.70-73 deg.C, 55.2mg. 1H NMR(400MHz，CDCl 3)δ7.40-7.18(m，14H)，6.80(s，1H)，5.10(s，1H)，3.36-3.32(m，1H)，3.14-3.09(m，1H)，2.37(s，3H)，1.10(t，J＝6.8Hz，3H). 13C NMR(100MHz，CDCl 3)δ148.1，139.1，139.0，137.1，135.4，130.5，129.4，128.9，128.2，128.2，128.0，128.0，127.8，127.1，75.0，64.3，21.1，15.0.ESI-MS m/z(％)368(100)[M+H] +；Anal.Calcd for C 25H 24N 2O C，81.49；H，6.57；N，7.60；Found：C，81.49；H，6.57；N，7.60.
Example 3: 5- (ethoxy (phenyl) methyl) -2-phenyl-1- (p-tolyl) -1H-imidazole (yield 83%)
Browu oil.61.1mg. 1H NMR(400MHz，CDCl 3)δ7.40-7.31(m，8H)，7.24-7.19(m，6H)，6.79(s，1H)，5.09(s，1H)，3.37-3.30(m，1H)，3.16-3.08(m，1H)，2.44(s，3H)，1.10(t，J＝6.8Hz，3H). 13C NMR(100MHz，CDCl 3)δ148.4，139.2，138.8，135.6，134.6，130.6，129.8，128.9，128.4，128.3，128.1，128.0，127.9，127.1，75.0，64.4，21.3，15.1.ESI-MS m/z(％)368(100)[M+H] +；Anal.Calcd for C 25H 24N 2O C，81.49；H，6.57；N，7.60；Found：C，81.49；H，6.57；N，7.60.
Example 4: 5- (ethoxy (phenyl) methyl) -1- (4-fluorophenyl) -2-phenyl-1H-imidazole (yield 81%)
Figure BSA0000146317310000093
Brown oil.60.3mg. 1H NMR(400MHz，CDCl 3)δ7.36-7.19(m，12H)，7.12-7.08(m，2H)，6.81(s，1H)，5.12(s，1H)，3.39-3.32(m，1H)，3.18-3.10(m，1H)，1.07(t，J＝6.8Hz，3H). 13C NMR(100MHz，CDCl 3)δ163.7(d，J＝248)，148.7，138.8，135.4，133.3，133.3，130.3，129.2，128.5，128.4，128.2，128.0，127.1，116.2，116.0，75.1，64.4，15.1.ESI-MS m/z(％)372(100)[M+H] +；Anal.Calcd for C 24H 21FN 2O C，77.40；H，5.68；N，7.52；Found：C，77.40；H，5.68；N，7.52.
Example 5: 1- (3-chlorophenyl) -5- (ethoxy (phenyl) methyl) -2-phenyl-1H-imidazole (74% yield)
Figure BSA0000146317310000101
Brown oil.57.6mg. 1H NMR(400MHz，CDCl 3)δ7.44-7.21(m，14H)，6.78(s，1H)，5.11(s，1H)，3.41-3.33(m，1H)，3.18-3.11(m，1H)，1.13(t，J＝6.8Hz，3H). 13C NMR(100MHz，CDCl 3)δ148.5，138.6，138.5，135.3，134.7，130.1，129.4，129.0，128.5，128.4，128.2，128.0，127.1，75.0，64.4，15.1.ESI-MS m/z(％)389(100)[M+H] +；Anal.Calcd forC 24H 21ClN 2O C，74.12；H，5.44；N，7.20；Found：C，77.12；H，5.44；N，7.20.
Example 6: 1- (4-chlorophenyl) -5- (ethoxy (phenyl) methyl) -2-phenyl-1H-imidazole (yield 72%)
Figure BSA0000146317310000102
Brown solid，m.p.104-106℃.56.0mg. 1H NMR(400MHz，CDCl 3)δ7.40-7.31(m，9H)，7.24-7.15(m，5H)，6.81(s，1H)，5.12(s，1H)，3.39-3.32(m，1H)，3.19-3.11(m，1H)，1.07(t，J＝7.2Hz，3H). 13C NMR(100MHz，CDCl 3)δ148.6，138.8，135.9，134.7，130.2，129.8，129.4，129.4，128.4，128.4，128.2，128.0，127.1，75.0，64.4，15.1.ESI-MS m/z(％)389(100)[M+H] +；Anal.Calcd for C 24H 21ClN 2O C，74.12；H，5.44；N，7.20；Found：C，77.12；H，5.44；N，7.20.
Example 7: 1- (3-bromophenyl) -5- (ethoxy (phenyl) methyl) -2-phenyl-1H-imidazole (78% yield)
Figure BSA0000146317310000103
Brown oil.67.5mg. 1H NMR(400MHz，CDCl 3)δ7.59(d，J＝7.6Hz，2H)，7.38-7.12(m，12H)，6.78(s，1H)，5.12(s，1H)，3.41-3.33(m，1H)，3.19-3.12(m，1H)，1.14(t，J＝6.4Hz，3H). 13C NMR(100MHz，CDCl 3)δ148.5，138.6，138.6，135.3，131.9，130.3，130.1，129.4，128.5，128.4，128.3，128.1，127.1，122.4，75.0，64.4，15.1.ESI-MS m/z(％)433(100)[M+H] +；Anal.Calcd for C 24H 21BrN 2O C，66.52；H，4.88；N，6.46；Found：C，66.52；H，4.88；N，6.46.
Example 8: 1- (3, 4-dichlorophenyl) -5- (ethoxy (phenyl) methyl) -2-phenyl-1H-imidazole (yield 81%)
Brown oil.68.5mg. 1H NMR(400MHz，CDCl 3)δ7.44-7.25(m，12H)，7.04(d，J＝10.8Hz，1H)，6.40(s，1H)，5.12(s，1H)，3.43-3.36(m，1H)，3.25-3.17(m，1H)，1.17(t，J＝7.2Hz，3H). 13C NMR(100MHz，CDCl 3)δ148.7，138.5，136.7，135.2，133.2，133.0，130.7，129.8，129.7，128.7，128.5，128.4，128.4，128.1，127.0，75.0，64.43，15.1.ESI-MSm/z(％)423(100)[M+H] +；Anal.Calcd for C 24H 20Cl 2N 2O C，68.09；H，4.76；N，6.62；Found：C，68.09；H，4.76；N，6.62.
Example 9: 5- (ethoxy (phenyl) methyl) -1-phenyl-2- (m-tolyl) -1H-imidazole (yield 76%)
Figure BSA0000146317310000111
Brown oil.55.9mg. 1H NMR(400MHz，CDCl 3)δ7.45-7.28(m，11H)，7.05-7.00(m，3H)，6.80(s，1H)，5.12(s，1H)，3.37-3.29(m，1H)，3.13-3.05(m，1H)，2.24(s，3H)，1.08(t，J＝7.2Hz，3H). 13C NMR(100MHz，CDCl 3)δ148.6，139.0，137.8，137.4，135.4，130.3，129.4，129.2，129.0，128.9，128.8，128.3，127.9，127.8，127.2，125.3，75.1，64.4，21.3，15.1.ESI-MS m/z(％)368(100)[M+H] +；Anal.Calcd for C 25H 24N 2O C，81.49；H，6.57；N，7.60；Found：C，81.49；H，6.57；N，7.60.
Example 10: 5- (ethoxy (phenyl) methyl) -1-phenyl-2- (p-toluene) -1H-imidazole (66% yield)
Figure BSA0000146317310000112
Brown solid，m.p.85-87℃.48.6mg. 1H NMR(400MHz，CDCl 3)δ7.41(d，J＝3.2Hz，3H)，7.36-7.25(m，9H)，6.02(d，J＝8.0Hz，2H)，6.76(s，1H)，5.11(s，1H)，3.36-3.29(m，1H)，3.12-3.04(m，1H)，2.28(s，3H)，1.07(t，J＝6.8Hz，3H). 13C NMR(100MHz，CDCl 3)δ148.6，139.1，138.1，137.5，135.2，129.2，128.9，128.8，128.7，128.3，127.9，127.7，127.2，75.1，64.4，21.2，15.1.ESI-MS m/z(％)368(100)[M+H] +；Anal.Calcd for C 25H 24N 2OC，81.49；H，6.57；N，7.60；Found：C，81.49；H，6.57；N，7.60.
Example 11: 5- (ethoxy (phenyl) methyl) -1- (4-fluorophenyl) -2- (m-toluene) -1H-imidazole (yield 81%)
Figure BSA0000146317310000113
Brown oil.62.5mg. 1H NMR(400MHz，CDCl 3)δ7.34-7.30(m，7H)，7.12-7.06(m，5H)，6.81(s，1H)，5.12(s，1H)，3.39-3.32(m，1H)，3.16-3.11(m，1H)，2.26(s，3H)，1.11(t，J＝7.2Hz，3H). 13C NMR(100MHz，CDCl 3)δ163.7(d，J＝248Hz)，148.8，138.8，138.0，135.3，133.4，133.3，130.0，129.4，129.2，129.0，128.4，128.0，127.9，127.1，125.3，116.2，115.9，75.1，64.4，21.3，15.1.ESI-MS m/z(％)386(100)[M+H] +；Anal.Calcd forC 25H 23FN 2O C，77.70；H，6.00；N，7.25；Found：C，77.70；H，6.00；N，7.25.
Example 12: 5- (ethoxy (phenyl) methyl) -1, 2-di-m-toluene-1H-imidazole (74% yield)
Figure BSA0000146317310000114
Browr oil.56.7mg. 1H NMR(400MHz，CDCl 3)δ7.36-7.22(m，9H)，7.02-6.76(m，4H)，6.76(s，1H)，5.06(s，1H)，3.35-3.27(m，1H)，3.11-3.04(m，1H)，2.34(s，3H)，2.23(s，3H)，1.07(t，J＝7.2Hz，3H). 13C NMR(100MHz，CDCl 3)δ148.4，139.2，139.2，137.8，137.3，135.4，130.4，129.5，129.3，129.0，128.9，128.6，128.3，127.9，127.8，127.2，125.2，75.1，64.4，21.4，21.3，15.1.ESI-MS m/z(％)383(100)[M+H] +；Anal.Calcd for C 26H 26N 2O C，81.64；H，6.85；N，7.32；Found：C，81.64；H，6.85；N，7.32.
Example 13: 1- (3-chlorophenyl) -5- (ethoxy (phenyl) methyl) -2- (m-toluene) -1H-imidazole (yield 70%)
Figure BSA0000146317310000121
Brown oil.56.4mg. 1H NMR(400MHz，CDCl 3)δ7.42-7.28(m，10H)，7.05-6.74(m，3H)，6.74(s，1H)，5.08(s，1H)，3.38-3.30(m，1H)，3.16-3.08(m，1H)，2.24(s，3H)，1.11(t，J＝6.8Hz，3H). 13C NMR(100MHz，CDCl 3)δ148.7，138.7，138.5，138.0，135.2，134.7，130.0，129.8，129.5，129.3，129.2，129.0，128.4，128.0，128.0，127.1，125.0，75.0，64.4，21.3，15.1.ESI-MS m/z(％)403(100)[M+H] +；Anal.Calcd for C 25H 23ClN 2O C，74.52；H，5.75；N，6.95；Found：C，74.52；H，5.75；N，6.95.
Example 14: 1- (4-chlorophenyl) -5- (ethoxy (phenyl) methyl) -2- (m-toluene) -1H-imidazole (85% yield)
Figure BSA0000146317310000122
Brown oil.68.5mg. 1H NMR(400MHz，CDCl 3)δ7.41-31(m，10H)，7.08(d，J＝5.2Hz，2H)，7.00(t，J＝4.0Hz，1H)，6.77(s，1H)，5.11(s，1H)，3.41-3.33(m，1H)，3.19-3.11(m，1H)，2.27(s，3H)，1.13(t，J＝6.8Hz，3H). 13C NMR(100MHz，CDCl 3)δ148.7，138.7，138.6，138.0，135.2，134.7，130.0，129.9，129.4，129.3，129.3，128.9，128.4，128.0，128.0，127.1，125.3，75.0，64.4，21.3，15.1.ESI-MS m/z(％)403(100)[M+H] +；Anal.Calcd forC 25H 23ClN 2O C，74.52；H，5.75；N，6.95；Found：C，74.52；H，5.75；N，6.95.
Example 15: 1- (3-bromophenyl) -5- (ethoxy (phenyl) methyl) -2- (m-toluene) -1H-imidazole (77% yield)
Figure BSA0000146317310000123
Brown oil.68.8mg. 1H NMR(400MHz，CDCl 3)δ7.58(d，J＝7.2Hz，2H)，7.35-7.32(m，6H)，7.28(t，J＝8.0Hz，1H)，7.15-6.78(m，4H)，6.78(s，1H)，5.11(s，1H)，3.41-3.33(m，1H)，3.20-3.12(m，1H)，2.27(s，3H)，1.14(t，J＝6.8Hz，3H). 13C NMR(100MHz，CDCl 3)δ148.7，138.7，138.6，138.0，135.2，131.9，130.3，129.8，129.5，129.3，129.2，128.4，128.0，128.0，127.1，125.4，122.4，75.0，64.4，21.3，15.1.ESI-MS m/z(％)447(100)[M+H] +；Anal.Calcd for C 25H 23BrN 2O C，67.12；H，5.18；N，6.26；Found：C，67.12；H，5.18；N，6.26.
Example 16: 1- (3-bromophenyl) -5- (ethoxy (phenyl) methyl) -2- (4-m-ethoxyphenyl) -1H-imidazole (66% yield)
Figure BSA0000146317310000124
Brown oil.61.1mg. 1H NMR(400MHz，CDCl 3)δ7.57(d，J＝8.0Hz，2H)，7.35-7.22(m，8H)，7.12(d，J＝7.6Hz，1H)，6.75(d，J＝8.8Hz，3H)，5.07(s，1H)，3.74(s，3H)，3.37-3.30(m，1H)，3.16-3.08(m，1H)，1.09(s，3H). 13C NMR(100MHz，CDCl 3)δ159.8，148.5，138.7，138.7，134.9，131.9，130.3，129.9，129.0，128.4，128.0，127.1，122.5，113.7，75.0，64.4，55.2，15.1.ESI-MS m/z(％)463(100)[M+H] +；Anal.Calcd for C 25H 23BrN 2O 2C，64.80；H，5.00；N，6.05；Found：C，64.80；H，5.00；N，6.05.
Example 17: 5- (m-ethoxy (phenyl) methyl) -1, 2-diphenyl-1H-imidazole (73% yield)
Figure BSA0000146317310000131
Yellow oil.67.6mg. 1H NMR(400MHz，Acetone)δ7.51(d，J＝3.2Hz，3H)，7.43-7.30(m，10H)，7.23(t，J＝6.4Hz，3H)，5.10(s，1H)，3.06(s，3H). 13C NMR(100MHz，Acetone)δ206.4，140.4，130.4，130.0，129.3，129.1，129.1，128.9，128.3，77.7，56.9.ESI-MS m/z(％)463(100)[M+H] +；Anal.Calcd for C 23H 20N 2O C，81.15；H，5.92；N，8.23；Found：C，81.15；H，5.92；N，8.23.
Example 18: 5- (butoxy (phenyl) methyl) -1, 2-diphenyl-1H-imidazole (yield 81%)
Figure BSA0000146317310000132
Brown oil.62.0mg. 1H NMR(400MHz，CDCl 3)δ7.38(d，J＝4.4Hz，3H)，7.35-7.25(m，9H)，7.15(d，J＝7.2Hz，3H)，6.78(s，1H)，5.08(s，1H)，3.26-3.20(m，1H)，3.04-2.98(m，1H)，1.43-1.36(m，2H)，1.25(m，2H)，0.81(t，J＝7.2Hz，3H). 13C NMR(100MHz，CDCl 3)δ148.2，139.0，137.1，135.3，130.3，129.0，128.9，128.6，128.2，128.1，128.0，127.9，127.7，127.0，75.0，68.6，31.6，19.2，13.7.ESI-MS m/z(％)383(100)[M+H] +；Anal.Calcdfor C 26H 26N 2O C，81.64；H，6.85；N，7.32；Found：C，81.64；H，6.85；N，7.32.
Example 19: 5- ((furan-2-ylmethoxyethoxy) (phenyl) methyl) -1, 2-diphenyl-1H-imidazole (yield 68%)
Figure BSA0000146317310000133
Brown oil.55.9mg. 1H NMR(400MHz，CDCl 3)δ7.39(d，J＝8.0Hz，3H)，7.35-7.30(m，9H)，7.22-7.15(m，4H)，6.86(s，1H)，6.27(d，J＝5.2Hz，1H)，6.12(d，J＝3.2Hz，1H)，5.22(s，1H)，4.31(d，J＝12.4Hz，1H)，4.10(d，J＝12.4Hz，1H). 13C NMR(100MHz，CDCl 3)δ151.1，142.8，138.2，136.9，134.8，130.1，129.2，128.8，128.4，128.4，128.3，128.1，128.1，127.3，110.2，109.5，74.1，62.3.ESI-MS m/z(％)406(100)[M+H] +；Anal.Calcd forC 27H 22N 2O 2C，79.78；H，5.46；N，6.89；Found：C，79.78；H，5.46；N，6.89.
Example 20: 5- ((benzyloxy) (phenyl) methyl) -1, 2-diphenyl-1H-imidazole (yield 84%)
Figure BSA0000146317310000134
Yellow solid，m.p.85-87℃.70.1mg. 1H NMR(400MHz，CDCl 3)δ7.44-7.36(m，10H)，7.32-7.27(m，3H)，7.24-7.13(m，7H)，6.94(s，1H)，5.31(s，1H)，4.39(d，J＝12.0Hz，1H)，4.17(d，J＝12.0Hz，1H). 13C NMR(100MHz，CDCl 3)δ148.4，138.6，137.4，137.0，134.9，130.3，129.3，129.1，128.6，128.3，128.3，128.2，128.1，127.9，127.9，127.5，127.2，74.5，70.6.ESI-MS m/z(％)417(100)[M+H] +；Anal.Calcd for C 29H 24N 2O C，83.63；H，5.81；N，6.73；Found：C，83.63；H，5.81；N，6.73.
Example 21: 5- ((allyloxy) (phenyl) methyl) -1, 2-diphenyl-1H-imidazole (yield 66%)
Figure BSA0000146317310000141
Brown oil.48.3mg. 1H NMR(400MHz，CDCl 3)δ7.40(d，J＝8.4Hz，3H)，7.36-7.27(m，8H)，7.19(t，J＝6.8Hz，4H)，6.84(s，1H)，5.67-5.57(m，1H)，5.17(s，1H)，5.15-5.05(m，2H)，3.84-3.80(m，1H)，3.62-3.57(m，1H). 13C NMR(100MHz，CDCl 3)δ148.4，138.6，137.1，135.1，134.1，130.3，129.2，129.1，128.8，128.4，128.3，128.2，128.0，127.9，127.2，117.3，74.2，69.6.ESI-MS m/z(％)366(100)[M+H] +；Anal.Calcd for C 25H 22N 2O C，81.94；H，6.05；N，7.64；Found：C，81.94；H，6.05；N，7.64.
Example 22: 5- (Isopropoxy (phenyl) methyl) -1, 2-diphenyl-1H-imidazole (yield 76%)
Figure BSA0000146317310000142
Brown solid，m.p.131-133℃.55.2mg. 1H NMR(400MHz，CDCl 3)δ7.42(d，J＝6.0Hz，2H)，7.34-7.29(m，8H)，7.24(d，J＝2.0Hz，2H)，7.19(t，J＝7.2Hz，3H)，6.79(s，1H)，5.29(s，1H)，3.43-3.37(m，1H)，0.99(d，J＝6.0Hz，3H)，0.72(d，J＝6.0Hz，3H). 13C NMR(100MHz，CDCl 3)δ148.2，139.6，137.1，135.5，130.2，129.2，129.0，128.9，128.4，128.3，128.2，128.0，127.8，127.2，72.0，69.1，22.8，20.7.ESI-MS m/z(％)368(100)[M+H] +；Anal.Calcdfor C 25H 24N 2O C，81.49；H，6.57；N，7.60；Found：C，81.49；H，6.57；N，7.60.
Example 23: 5- (phenoxy (phenyl) methyl) -1, 2-diphenyl-1H-imidazole (yield 73%)
Figure BSA0000146317310000143
Yellow solid，m.p.135-136℃.58.7mg. 1H NMR(400MHz，CDCl 3)δ7.37(d，J＝7.6Hz，5H)，7.31(t，J＝7.2Hz，6H)，7.21(t，J＝7.2Hz，4H)，7.13-7.08(m，2H)，6.90-6.82(m，2H)，6.66(s，2H)，5.96(s，1H). 13C NMR(100MHz，CDCl 3)δ157.3，148.7，138.0，136.8，134.5，130.1，129.8，129.3，129.2，128.8，128.5，128.4，128.4，128.10，128.1，126.8，121.2，115.8，73.5.ESI-MS m/z(％)402(100)[M+H] +；Anal.Calcd for C 28H 22N 2O C，83.56；H，5.51；N，6.96；Found：C，83.56；H，5.51；N，6.96.
Example 24: 5- (Phenoxy (phenyl) methyl) -2-phenyl-1- (m-toluene) -1H-imidazole (yield 80%)
Figure BSA0000146317310000144
Yellow oil.66.7mg. 1H NMR(400MHz，CDCl 3)δ7.39-7.35(m，4H)，7.33-7.27(m，3H)，7.19(d，J＝7.2Hz，3H)，7.13-7.03(m，6H)，6.87-6.81(m，2H)，6.66(d，J＝7.6Hz，2H)，5.93(s，1H)，2.30(s，3H). 13C NMR(100MHz，CDCl 3)δ157.5，148.7，138.9，138.3，134.6，134.2，130.4，130.0，129.8，129.2，128.5，128.5，128.3，128.1，128.1，126.9，121.2，115.9，73.6，21.2.ESI-MS m/z(％)417(100)[M+H] +；Anal.Calcd for C 29H 24N 2O C，83.63；H，5.81；N，6.73；Found：C，83.63；H，5.81；N，6.73.
Example 25: 5- (Phenoxy (phenyl) methyl) -2-phenyl-1- (p-toluene) -1H-imidazole (yield 71%)
Figure BSA0000146317310000151
Yellow oil.59.2mg. 1H NMR(400MHz，CDCl 3)δ7.42-7.37(m，4H)，7.35-7.30(m，3H)，7.24-7.08(m，9H)，6.86(t，J＝7.2Hz，2H)，6.69(d，J＝8.0Hz，2H)，5.92(s，1H)，2.14(s，3H). 13C NMR(100MHz，CDCl 3)δ157.3，148.5，138.1，136.6，130.2，129.5，129.2，129.0，128.4，128.3，128.3，128.0，126.8，121.1，115.6，20.9.ESI-MS m/z(％)417(100)[M+H] +；Anal.Calcd for C 29H 24N 2O C，83.63；H，5.81；N，6.73；Found：C，83.63；H，5.81；N，6.73.
Example 26: 1- (3-chlorophenyl) -5- (phenoxy (phenyl) methyl) -2-phenyl-1H-imidazole (yield 75%)
Figure BSA0000146317310000152
Brown oil.65.6mg. 1H NMR(400MHz，CDCl 3)δ7.36(d，J＝8.0Hz，4H)，7.29(d，J＝7.6Hz，3H)，7.25-7.19(m，5H)，7.15-7.08(m，3H)，7.06(d，J＝7.6Hz，1H)，6.87(t，J＝8.0Hz，2H)，6.69(d，J＝8.0Hz，2H)，5.98(s，1H). 13C NMR(100MHz，CDCl 3)δ157.1，148.7，137.9，137.7，134.8，134.3，130.1，130.0，129.8，129.2，129.0，128.5，128.4，128.4，128.2，128.1，126.6，121.3，115.5，73.2.ESI-MS m/z(％)437(100)[M+H] +；Anal.Calcdfor C 28H 21ClN 2O C，76.97；H，6.84；N，6.41；Found：C，76.97；H，6.84；N，6.41.
Example 27: 1- (3-bromophenyl) -5- (phenoxy (phenyl) methyl) -2-phenyl-1H-imidazole (yield 68%)
Brown oil.65.4mg. 1H NMR(400MHz，CDCl 3)δ7.42(t，J＝3.6Hz，2H)，7.39-7.29(m，8H)，7.23(d，J＝7.6Hz，2H)，7.17-7.11(m，4H)，6.88(t，J＝7.2Hz，2H)，6.72(d，J＝8.0Hz，2H)，5.99(s，1H). 13C NMR(100MHz，CDCl 3)δ157.2，138.2，137.8，134.4，132.0，130.4，130.2，129.9，129.4，128.7，128.8，128.5，128.3，128.2，126.7，121.4，115.7，73.3.ESI-MSm/z(％)481(100)[M+H] +；Anal.Calcd for C 28H 21BrN 2O C，69.86；H，4.40；N，5.82；Found：C，69.86；H，4.40；N，5.82.
Example 28: 1- (4-fluorophenyl) -5- (phenoxy (phenyl) methyl) -2- (p-toluene) -1H-imidazole (yield 76%)
Figure BSA0000146317310000154
Yellow oil.81.3mg. 1H NMR(400MHz，CDCl 3)δ7.35-7.26(m，5H)，7.22(d，J＝8.0Hz，2H)，7.19-7.08(m，4H)，7.00(d，J＝8.0Hz，2H)，6.97-6.82(m，4H)，6.67(d，J＝7.6Hz，2H)，5.95(s，1H)，2.25(s，3H). 13C NMR(100MHz，CDCl 3)δ163.5(d，J＝250Hz)，157.2，149.1，138.4，137.9，134.1，132.9，132.9，130.0，129.2，128.9，128.4，128.3，128.1，127.2，126.7，121.3，116.3，116.1，115.6，73.3，21.1.ESI-MS m/z(％)435(100)[M+H] +；Anal.Calcd for C 29H 23FN 2O C，80.16；H，5.34；N，6.45；Found：C，80.16；H，5.34；N，6.45.
Example 29: 5- (ethoxy (o-toluene) methyl) -1, 2-diphenyl-1H-imidazole (yield 68%)
Figure BSA0000146317310000161
Brown oil.50.0mg. 1H NMR(400MHz，CDCl 3)δ7.55(d，J＝7.2Hz，1H)，7.46(s，4H)，7.36(d，J＝6.0Hz，2H)，7.27(d，J＝7.6Hz，1H)，7.25-7.23(m，1H)，7.23-7.17(m，4H)，7.12(d，J＝7.0Hz，1H)，6.62(s，1H)，5.18(s，1H)，3.34-3.27(m，1H)，2.99-2.92(m，1H)，2.11(s，3H)，1.04(t，J＝7.2Hz，3H). 13C NMR(100MHz，CDCl 3)δ148.3，137.3，136.8，135.5，134.6，130.4，130.3，129.3，129.2，128.9，128.3，128.2，128.0，127.6，126.2，126.1，71.7，64.6，18.8，15.1.ESI-MS m/z(％)368(100)[M+H] +；Anal.Calcd for C 25H 24N 2O C，81.49；H，6.57；N，7.60；Found：C，81.49；H，6.57；N，7.60.
Example 30: 5- (ethoxy (m-toluene) methyl) -1, 2-diphenyl-1H-imidazole (yield 74%)
Figure BSA0000146317310000162
Brown oil.54.5mg. 1H NMR(400MHz，CDCl 3)δ7.42(d，J＝5.2Hz，3H)，7.34(d，J＝8.0Hz，3H)，7.25-7.09(m，7H)，6.92(d，J＝6.0Hz，1H)，6.80(d，J＝8.0Hz，1H)，5.05(s，1H)，3.36-3.27(m，1H)，3.09-3.01(m，1H)，2.29(s，3H)，1.03(t，J＝7.2Hz，3H). 13C NMR(100MHz，CDCl 3)δ148.1，138.7，137.9，137.8，137.2，130.2，129.5，129.1，129.1，128.8，128.7，128.4，128.2，128.2，128.0，127.8，124.9，124.2，75.0，64.3，21.4，21.3，15.0.ESI-MS m/z(％)368(100)[M+H] +；Anal.Calcd for C 25H 24N 2O C，81.49；H，6.57；N，7.60；Found：C，81.49；H，6.57；N，7.60.
Example 31: 5- (ethoxy (p-toluene) methyl) -1, 2-diphenyl-1H-imidazole (yield 75%)
Brown solid，m.p.100-101℃.55.2mg. 1H NMR(400MHz，CDCl 3)δ7.43(d，J＝3.2Hz，3H)，7.34(d，J＝6.0Hz，3H)，7.23-7.14(m，8H)，6.77(s，1H)，5.04(s，1H)，3.32-3.25(m，1H)，3.06-2.98(m，1H)，2.36(s，3H)，1.01(t，J＝7.0Hz，3H). 13C NMR(100MHz，CDCl 3)δ148.2，137.6，137.3，135.8，135.6，130.4，129.1，129.0，128.8，128.7，128.4，128.1，128.0，127.1，74.8，64.2，21.1，15.0.ESI-MS m/z(％)368(100)[M+H] +；Anal.Calcd forC 25H 24N 2O C，81.49；H，6.57；N，7.60；Found：C，81.49；H，6.57；N，7.60.
Example 32: 5- ((3, 5-dimethylphenyl) (ethoxy) methyl) -1, 2-diphenyl-1H-imidazole (yield 81%)
Figure BSA0000146317310000164
Yellow oil.62.0mg. 1H NMR(400MHz，CDCl 3)δ7.42(d，J＝4.4Hz，3H)，7.34(d，J＝5.6Hz，3H)，7.20-7.15(m，4H)，6.92(d，J＝3.2Hz，3H)，6.81(s，1H)，5.02(s，1H)，3.36-3.28(m，1H)，3.09-3.02(m，1H)，2.29(s，6H)，1.03(t，J＝7.0Hz，3H). 13C NMR(100MHz，CDCl 3)δ148.2，138.8，137.7，137.3，135.6，130.5，129.5，129.1，128.8，128.7，128.4，128.1，128.0，124.9，75.1，64.3，21.2，15.0.ESI-MS m/z(％)383(100)[M+H] +；Anal.Calcd forC 26H 26N 2O C，81.64；H，6.85；N，7.32；Found：C，81.64；H，6.85；N，7.32.
Example 33: (1, 2-Diphenyl-1H-imidazol-5-yl) (phenyl) methyl acetate (73% yield)
Figure BSA0000146317310000171
Yellow solid，m.p.147-149℃.53.7mg. 1H NMR(400MHz，CDCl 3)δ7.40(d，J＝6.4Hz，3H)，7.35(d，J＝6.0Hz，2H)，7.32-7.28(m，5H)，7.19(d，J＝7.6Hz，5H)，6.95(s，1H)，6.67(s，1H)，1.89(s，3H). 13C NMR(100MHz，CDCl 3)δ169.2，148.6，137.3，136.7，133.1，130.0，129.5，129.5，129.0，128.3，128.3，128.0，127.1，69.0，20.7.ESI-MS m/z(％)368(100)[M+H] +；Anal.Calcd for C 24H 20N 2O 2C，78.24；H，5.47；N，7.60；Found：C，78.24；H，5.47；N，7.60.
Example 34: (1, 2-Diphenyl-1H-imidazol-5-yl) (phenyl) methylbenzoate (yield 77%)
Brown oil.66.4mg. 1H NMR(400MHz，CDCl 3)δ7.96(d，J＝7.2Hz，2H)，7.55(t，J＝7.6Hz，1H)，7.44-7.30(m，12H)，7.23-7.17(m，5H)，7.08(s，1H)，6.92(s，1H). 13C NMR(100MHz，CDCl 3)δ164.8，148.6，137.4，136.5，133.1，129.8，129.8，129.6，129.6，129.5，129.5，129.1，128.5，128.4，128.4，128.4，128.3，128.1，127.0，69.4.ESI-MS m/z(％)431(100)[M+H] +；Anal.Calcd for C 29H 22N 2O 2C，80.91；H，5.15；N，7.43；Found：C，80.91；H，5.15；N，7.43.
Example 35: n- ((1, 2-Diphenyl-1H-imidazol-5-yl) (phenyl) methyl) -N-phenylaniline (yield 44%)
Figure BSA0000146317310000173
Brown oil.42.1mg. 1H NMR(400MHz，CDCl 3)δ7.34(t，J＝7.2Hz，3H)，7.26-7.14(m，10H)，7.09-7.02(m，5H)，6.97-6.88(m，7H)，6.80(s，1H)，5.01(s，1H). 13C NMR(100MHz，CDCl 3)δ147.3，143.1，141.7，137.6，136.9，133.8，129.7，129.3，129.2，128.8，128.7，128.3，128.3，128.2，128.1，126.7，120.9，117.8，117.6，47.3.ESI-MS m/z(％)478(100)[M+H] +；Anal.Calcd for C 34H 27N 3C，85.50；H，5.70；N，8.80；Found：C，85.50；H，5.70；N，8.80.
Toxicity test:
healthy Kunming mice are selected and provided by the experimental center of Guangdong university of pharmacy. The mice are raised in nontoxic plastic boxes, 5 mice are fed in each box, the female and male cages are separated, the padding is replaced 1 time every day, the mice can freely eat and drink water, the room temperature is kept at 18-20 ℃, and the mice are naturally illuminated. The drug was dissolved in 0.9% aqueous sodium chloride and the test substance dose was expressed in mg/kg. The medicine is administrated by intraperitoneal injection according to the following dose, the administration volume is 0.1mL/10g, and the medicine is administrated according to the following dose: 50. 100, 150, 200 and 300 mg/kg. Animals were observed daily for 10 consecutive days after dosing to record appearance, mental, diet, sleep, activity and daily mortality distribution, and LD50 was calculated according to the Bliss method. After the administration of the high concentration group, mice are listened, the feces before death are not shaped, emaciation, hair erection and mass atrophy are still.
Figure BSA0000146317310000181
As can be seen from the above table, the compounds of formula I of the present invention have lower toxicity.
Inhibition of tumor cells by compounds of formula I:
cells in logarithmic growth phase were digested, counted and plated in 96-well plates at 100. mu.L/well. After 24h of culture, tumor cells were treated with the complexes at different concentrations. After 72h of drug action, the supernatant was removed and 100. mu.L of MTT (1 m) was added to each wellg/mL), continuously culturing for 4h, removing the supernatant, adding 100 mu L DMSO into each hole, uniformly mixing by oscillation, and measuring the absorbance value at 570nm by using a microplate reader. And calculating the inhibition rate. Calculating the formula: inhibition (%) × (control absorbance value-administration absorbance value)/(control absorbance value-blank absorbance value) × 100%. Using IC 50Calculating software (university of Chinese medicine) to obtain half Inhibitory Concentration (IC) 50)。
The experimental tumor strains comprise human gastric cancer cells BGC, human cervical adenocarcinoma cells HeLa, human colon cancer cells HCT116, human lung adenocarcinoma cells A549, human lung cancer cells NCI-H460, human prostate cancer cells DU-145 and human breast cancer cells MDA-MB-231. The cells were purchased from cell banks of the Guangdong province microbial culture Collection. The results of the experiments are shown in the following table.
Figure BSA0000146317310000191

Claims (4)

1. A compound of formula I, characterized by the following:
Figure FSB0000184717870000011
the compound shown in the formula I is selected from the following compounds:
Figure FSB0000184717870000012
2. a composition comprising a compound of claim 1, and a pharmaceutically acceptable adjuvant or carrier.
3. The composition of claim 2, wherein: the dosage form is selected from plain tablet, film coated tablet, sugar coated tablet, intestine coated tablet, dispersible tablet, capsule, granule, oral solution or oral suspension.
4. Use of a compound according to claim 1 for the preparation of a medicament for the treatment of tumors or cancers of the stomach, cervix, colon, lung, breast and prostate.
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