CN108929292B - 2-methyl alkenyl substituted type secolignan derivative and medical application thereof - Google Patents
2-methyl alkenyl substituted type secolignan derivative and medical application thereof Download PDFInfo
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- CN108929292B CN108929292B CN201710387206.8A CN201710387206A CN108929292B CN 108929292 B CN108929292 B CN 108929292B CN 201710387206 A CN201710387206 A CN 201710387206A CN 108929292 B CN108929292 B CN 108929292B
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/58—One oxygen atom, e.g. butenolide
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- C07—ORGANIC CHEMISTRY
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- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
Abstract
The invention relates to a 2-methyl alkenyl substituted secolignan derivative and medical application thereof, in particular to a compound with a structure shown in a formula I or pharmaceutical application thereofThe pharmaceutically acceptable salt, a pharmaceutical composition containing the compound or the pharmaceutically acceptable salt thereof, application of the compound or the pharmaceutically acceptable salt thereof in preparing a medicine taking a JAK-STAT signal pathway as a target, and application of the compound or the pharmaceutically acceptable salt thereof in preventing and/or treating JAK-STAT signal pathway related diseases of a subject.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and relates to a 2-methylene substituted secolignan compound, a pharmaceutical composition containing the 2-methylene substituted secolignan compound and medical application thereof.
Background
Lignans are a class of natural products derived from the oxidative polymerization of phenylpropanoids, commonly referred to as dimers thereof. Secolignans are unusual lignans, one C in the lignans6-C3The units are subjected to ring-opening breakage and then are reconnected, so that the mother nucleus is changed into the structural type of dibenzyl butyrolactone, and Chen CM and the like separate the compounds from Peperomiajaponica for the first time in 1989. The lignan compounds known in nature are classified into 2-methyl-substituted type, 2-methylene-substituted type, 2-hydroxymethyl-substituted type, 2-acetoxymethyl-substituted type, and gamma-butyrolactone type in which the carbonyl group is reduced to a hydroxyl group, depending on the substitution pattern of 2-C on the gamma-butyrolactone ring and the carbonyl reduction. Among them, 2-methylene-substituted secolignans are more rare in nature, and only 5 compounds are separated from plant pepper and nettle at present. The literature reports that the schizolignan compounds pepromia pellucida B and pepromia pellucida E have strong growth inhibitory activity on various tumor cells.
Jak (janus kinase) is one of Protein Tyrosine Kinases (PTKs) that mediate a cascade of activation reactions of signaling protein molecules upon binding of cytokines to their receptors. Cytokines, growth factors, etc. bind to their respective receptors to activate JAKs, which in turn activate signal transducers and activators of transcription stat (signal transducer and activator) for transcription. STAT is a unique family of proteins capable of binding to DNA, and it has been found that there are 7 members of the STAT family, namely STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT 6. The JAK-STAT signal pathway is a common way for a plurality of cytokines and growth factors to transmit signals in cells, participates in a plurality of biological processes such as proliferation, differentiation, apoptosis, immune disorder, inflammation, tumorigenesis and the like of cells of an organism, and is widely researched at home and abroad in recent decades. Activation of the JAK-STAT signaling pathway contributes to the development of a variety of diseases including various solid tumors, lymphomas, leukemias, and a variety of inflammatory diseases. For example, gamma interferon (IFN- γ) mainly activates downstream gene transcription through STAT1 signaling pathway, promotes cellular immunity, humoral immunity, etc., and plays roles in resisting malignant tumor cell proliferation, virus, immune surveillance, and tumor suppression. However, IFN- γ is a possible causative agent of autoimmune diseases. Inhibition of persistently activated STAT1 may have therapeutic effects on autoimmune diseases, chronic inflammation and consequent tissue damage. Interleukin-6 (IL-6), Epidermal Growth Factor (EGF) and the like activate corresponding downstream genes to regulate processes of cell proliferation, apoptosis and the like mainly through STAT3 signal channels. The continuously activated STAT3 can promote the proliferation, survival and metastasis of tumor cells by inhibiting the anti-tumor immune response of the organism, and can also generate inflammation by promoting NF-kappa B, IL-6-GP130-JAK-STAT signals. The STAT3 which is continuously activated in the tumor cells is inhibited, so that the tumor cell apoptosis can be effectively promoted, and the development of tumors is inhibited. In addition, some liver injuries and neurological diseases are also associated with the JAK-STAT signaling pathway.
So far, no report that compounds with 2-methyl-type lignanoid structural skeleton have inhibitory activity on JAK-STAT signal pathway is found in related researches at home and abroad.
Disclosure of Invention
In the present invention, unless otherwise specified, scientific and technical terms used herein have the meanings that are commonly understood by those skilled in the art. Also, the laboratory procedures referred to herein are all conventional procedures widely used in the corresponding field. Meanwhile, in order to better understand the present invention, the definitions and explanations of related terms are provided below.
As used herein, the term "C1-4Alkoxy "means with C1-4Groups formed by alkyl-O-, including but not limited to C1-4Straight-chain or branched alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, C4Straight or branched alkoxy.
As used herein, the term "C2-5Alkenyloxy "means with C2-4Groups formed by alkenyl-O-means, including but not limited to C2-5Straight-chain or branched alkenyloxy radicals, e.g. vinyloxy, allyloxy, propenyloxy, C4-5Straight-chain or branched alkenyloxy (e.g. 2-methyl-2-butenyl-O-, 2-methyl-1-butenyl-O-, 3-methyl-1-butenyl-O).
As used herein, the term "C2-4Alkynyloxy "denotes with C2-4Groups formed by alkynyl-O-, including but not limited to C2-4Straight-chain or branched alkynyloxy, e.g. ethynyloxy, propynyloxy, propargyloxy, C4Straight or branched alkynyloxy.
As used herein, the term "C6-8The term "aromatic hydrocarbon oxy" means an alkoxy group represented by C6-8Examples of the aromatic group-O-include, but are not limited to, phenoxy and benzyloxy.
As used herein, the term "C1-12The fatty acyloxy group "means a group formed by removing a hydrogen atom from at least one carboxyl group of a fatty acid having 1 to 12 carbon atoms, which is a straight or branched fatty acid, a saturated fatty acid or an unsaturated fatty acid, and which has one or more carboxyl groups. Said C is2-12Aliphatic acyloxy groups include, but are not limited to, formyloxy, acetoxy, acryloyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, succinyloxy, octanoyloxy, lauroyloxy.
As used herein, the term "C1-4Fatty acyloxy group(s), "C1-5Fatty acyloxy group(s), "C1-8Fatty acyloxy group(s), "C1-12Fatty acyloxy group(s), "C3-5Fatty acyloxy group(s), "C3-6Fatty acyloxy group(s), "C6-10Fatty acyloxy group(s), "C7-9Fatty acyloxy group(s), "C9-12Fatty acyloxy groups "means respectively C1-12Among the fatty acyloxy groups, specific examples containing 1 to 5 carbon atoms, 1 to 8 carbon atoms, 1 to 12 carbon atoms, 3 to 5 carbon atoms, 3 to 6 carbon atoms, 6 to 10 carbon atoms, 7 to 9 carbon atoms, and 9 to 12 carbon atoms are given.
As used herein, the terms "linear fatty acyloxy group", "branched fatty acyloxy group", "saturated fatty acyloxy group", "unsaturated fatty acyloxy group", "linear saturated fatty acyloxy group", "branched saturated fatty acyloxy group", "linear unsaturated fatty acyloxy group", and "branched unsaturated fatty acyloxy group" respectively refer to specific examples in which the fatty acid forming the fatty acyloxy group is a linear fatty acid, a branched fatty acid, a saturated fatty acid, an unsaturated fatty acid, a linear saturated fatty acid, a branched saturated fatty acid, a linear unsaturated fatty acid, or a branched unsaturated fatty acid.
As used herein, the term "C6-8The "aromatic acyloxy group" means a group formed by removing a hydrogen atom from at least one carboxyl group of an aromatic carboxylic acid having 6 to 8 carbon atoms, such as benzoyloxy group, phenylacetyloxy group.
The term "pharmaceutically acceptable salt" as used herein refers to acidic functional groups (e.g., -COOH, -OH, -SO) present in the compounds of the present invention3H, etc.) with a suitable inorganic or organic cation (base), including salts with alkali or alkaline earth metals (e.g., sodium, potassium, magnesium or calcium salts), ammonium salts, and salts with nitrogen-containing organic bases; and basic functional groups present in the compounds of the invention (e.g. -NH)2Etc.) with a suitable inorganic or organic anion (acid), including salts with inorganic acids and salts with organic carboxylic acids.
As used herein, the term "room temperature" refers to 25 ± 5 ℃.
As used herein, the term "about" should be understood by those skilled in the art and will vary to some extent depending on the context in which it is used. If the use of the term is not clear to one of ordinary skill in the art based on the context in which the term is used, then "about" means no more than plus or minus 10% of the stated particular value or range.
The inventor successfully obtains the 2-methylene substituted type cleaverin compound with the structure shown in the formula I (shown in a figure 1) through creative labor and continuous efforts:
wherein, Arabic numerals on the ring structure represent corresponding index positions. The present inventors have also found that the compounds are capable of inhibiting the activity of the intracellular JAK-STAT signaling pathway, thereby providing the following invention:
in one aspect, the invention relates to a compound having the structure shown in formula I or a pharmaceutically acceptable salt thereof,
wherein the content of the first and second substances,
R1、R2each selected from hydroxy and the following optionally substituted with a substituent: c1-4Alkoxy radical, C2-5Alkenyloxy radical, C2-4Alkynyloxy, C6-8Aromatic oxyl radical, C1-12Fatty acyloxy, C6-8An aromatic acyloxy group, the substituent being selected from the group consisting of hydroxy, halogen (e.g., fluorine, chlorine, bromine, iodine), nitro, carboxy, benzyloxy, the number of the substituents being from 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6); or, R1And R2form-O- (CH)2)n-O- (n ═ 1 or 2);
R3、R4each selected from hydroxy and the following optionally substituted with a substituent: c1-4Alkoxy radical, C2-5Alkenyloxy radical, C2-4Alkynyloxy selected from hydroxy, halo (e.g., fluoro, chloro, bromo, iodo), nitro, carboxy, benzyloxy, the number of said substituents being from 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6);
R5、R6each selected from hydroxy and the following optionally substituted with a substituent: c1-4Alkoxy radical, C2-5Alkenyloxy radical, C2-4Alkynyloxy selected from hydroxy, halo (e.g., fluoro, chloro, bromo, iodo), nitro, carboxy, benzyloxy, the number of said substituents being from 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6); or, R5And R6form-O- (CH)2)n-O- (n ═ 1 or 2);
in certain embodiments, said C1-4Alkoxy is selected from methoxy, ethoxy, propoxy, isopropoxy, C4Straight or branched alkoxy.
In certain embodiments, said C2-5The alkenyloxy group is selected from the group consisting of vinyloxy, allyloxy, propenyloxy, C4-5Linear or branched alkenyloxy.
In certain embodiments, said C2-4The alkynyloxy is selected from the group consisting of ethynyloxy, propynyloxy, propargyloxy, C4Straight or branched alkynyloxy.
In certain embodiments, said C6-8The aromatic alkoxy is selected from phenoxy and benzyloxy.
In certain embodiments, said C1-12The fatty acyloxy is selected from C1-4Fatty acyloxy, C1-5Fatty acyloxy, C1-8Fatty acyloxy, C1-12Fatty acyloxy, C3-5Fatty acyloxy, C3-6Fatty acyloxy, C6-10Fatty acyloxy, C7-9Fatty acyloxy, C9-12A fatty acyloxy group.
In certain embodiments, the fatty acyloxy group is selected from: straight chain fatty acyloxy, branched chain fatty acyloxy, saturated fatty acyloxy, unsaturated fatty acyloxy, straight chain saturated fatty acyloxy, branched chain saturated fatty acyloxy, straight chain unsaturated fatty acyloxy, and branched chain unsaturated fatty acyloxy.
In certain embodiments, said C1-12The fatty acyloxy is selected from: formyloxy, acetoxy, acryloyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, octanoyloxy, succinyloxy, lauroyloxy.
In certain embodiments, said C1-12The fatty acyloxy group is substituted with a carboxyl group or a hydroxyl group.
In certain embodiments, said C substituted with carboxy or hydroxy1-12The fatty acyloxy is 3-hydroxy lauroyloxy.
In certain embodiments, said C6-8The aromatic acyloxy is selected from benzoyloxy and phenylacetyloxy.
In certain embodiments, said C6-8The aromatic acyloxy group is substituted with halogen, hydroxy or nitro.
In certain embodiments, the C substituted with halogen, hydroxy or nitro6-8The aromatic acyloxy is selected from galloyloxy, p-nitrobenzoyloxy, p-chlorobenzoyloxy, p-fluorobenzoyloxy.
In certain embodiments, R1、R2Each selected from the group consisting of hydroxy, methoxy, ethoxy, isopentenyloxy, formyloxy, acetoxy, acryloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, succinyloxy, octanoyloxy, lauroyloxy, 3-hydroxylauroyloxy, benzoyloxy, galloyloxy, p-nitrobenzoyloxy, p-chlorobenzoyloxy, p-fluorobenzoyloxy, or R1And R2form-O- (CH)2)n-O- (n ═ 1 or 2);
R3、R4each selected from C optionally substituted by a substituent1-3Alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy);
R5、R6each selected from C optionally substituted by a substituent1-3Alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy), or, R5And R6form-O- (CH)2)n-O- (n ═ 1 or 2);
the substituents are selected from hydroxyl, halogen (e.g. fluorine, chlorine, bromine, iodine), nitro, carboxyl, benzyloxy, the number of the substituents being 1-6 (e.g. 1, 2, 3, 4, 5 or 6).
In certain embodiments, the compounds satisfy the following conditions:
(1)R1-R6not simultaneously being methoxy, and
(2) when R is1、R3、R4Each is methoxy, and R5And R6Formation of-O-CH2when-O-is present, R2Is not a hydroxyl group.
In certain embodiments, R1、R2Each selected from the group consisting of hydroxy, methoxy, ethoxy, isopentenyloxy, acetoxy, benzoyloxy, galloyloxy, p-nitrobenzoyloxy;
R3、R4each selected from methoxy, ethoxy, propoxy, isopropoxy;
R5、R6each selected from methoxy, ethoxy, propoxy and isopropoxy, or, R5And R6form-O- (CH)2)n-O- (n ═ 1 or 2);
and, the compound satisfies the following condition:
(1)R1-R6not simultaneously being methoxy, and
(2) when R is1、R3、R4Each is methoxy, and R5And R6Formation of-O-CH2when-O-is present, R2Is not a hydroxyl group.
In certain embodiments, R1Is hydroxy or methoxy;
R2selected from the group consisting of hydroxy, methoxy, ethoxy, isopentenyloxy, acetoxy, benzoyloxy, galloyloxy, p-nitrobenzoyloxy;
R3、R4、R5、R6each is methoxy; or, R3、R4Each is methoxy, R5And R6Formation of-O-CH2-O-；
And, the compound satisfies the following condition:
(1)R1-R6not simultaneously being methoxy, and
(2) when R is1、R3、R4Each is methoxy, and R5And R6Formation of-O-CH2when-O-is present, R2Is not a hydroxyl group.
In certain embodiments, R1、R3、R4、R5、R6Each is methoxy, R2Is a hydroxyl group.
In certain embodiments, R2、R3、R4、R5、R6Each is methoxy, R1Is a hydroxyl group.
In certain embodiments, R1、R3、R4Each is methoxy, R2Is ethoxy, R5And R6Formation of-O-CH2-O-。
In certain embodiments, R1、R3、R4Each is methoxy, R2Is isopentenyloxy, R5And R6Formation of-O-CH2-O-。
In certain embodiments, R1、R3、R4Each is methoxy, R2Is acetoxy, R5And R6Formation of-O-CH2-O-。
In certain embodiments, R1、R3、R4Each is methoxy, R2Is galloyloxy, R5And R6Formation of-O-CH2-O-。
In certain embodiments, R1、R3、R4Each is methoxy, R2Is p-nitrobenzoyloxy, R5And R6Formation of-O-CH2-O-。
In certain embodiments, R1、R3、R4Each is methoxy, R2Is benzoyloxy, R5And R6Formation of-O-CH2-O-。
In one aspect, the present invention relates to a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof, optionally together with one or more pharmaceutical excipients.
The pharmaceutical excipients in the present application refer to excipients and additives used in the manufacture of pharmaceutical products and in the formulation of pharmaceutical formulations, and refer to substances which have been reasonably evaluated in terms of safety and which are included in pharmaceutical preparations, in addition to the active ingredient. The pharmaceutic adjuvant has important functions of solubilization, dissolution assistance, sustained and controlled release and the like besides excipient, carrier and stability improvement, and is an important component which may influence the quality, safety and effectiveness of the medicine. The medicinal adjuvants can be divided into natural, semi-synthetic and total synthetic according to source; according to their action and use, they can be divided into: solvents, propellants, solubilizers, solubilizing agents, emulsifiers, colorants, adhesives, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adherents, antioxidants, chelating agents, permeation promoters, pH regulators, buffers, plasticizers, surfactants, foaming agents, antifoaming agents, thickeners, encapsulating agents, humectants, absorbents, diluents, flocculants and deflocculants, filter aids, release retardants, and the like; according to the administration route, the medicine can be divided into oral administration, injection, mucous membrane, percutaneous or local administration, nasal or oral inhalation administration, ocular administration and the like. The same pharmaceutic adjuvant can be used for pharmaceutic preparations of different administration routes and has different functions and purposes.
The pharmaceutical composition of the present application may be formulated into various suitable dosage forms according to the administration route. The route of administration may be oral, parenteral or topical.
The pharmaceutical compositions of the present application may be administered in any manner, such as: oral, aerosol inhalation, rectal, nasal, topical, parenteral, such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion, or via an explanted reservoir; preferred modes of administration are oral, intraperitoneal or intravenous.
When administered orally, the pharmaceutical composition may be formulated into any orally acceptable dosage form including, but not limited to, tablets, capsules, granules, pills, syrups, oral solutions, oral suspensions, oral emulsions, and the like. Among these, carriers for tablets generally include lactose and corn starch, and additionally, lubricating agents such as magnesium stearate may be added. Diluents for use in capsules typically include lactose and dried corn starch. Oral suspensions are generally prepared by mixing the active ingredient with suitable emulsifying and suspending agents. Optionally, some sweetener, aromatic or colorant may be added into the above oral preparation.
When administered transdermally or topically, the pharmaceutical compositions may be formulated in the form of suitable ointments, lotions or liniments in which the active ingredient is suspended or dissolved in one or more carriers. Carriers that may be used in ointment formulations include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; lotions or liniments carriers that may be used include, but are not limited to: mineral oil, sorbitan monostearate, tween 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
The pharmaceutical composition can also be used in the form of injection, including injection, sterile powder for injection and concentrated solution for injection. Among the carriers and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. In addition, the sterilized fixed oil may also be employed as a solvent or suspending medium, such as a monoglyceride or diglyceride.
In certain embodiments, the compounds of the present invention, or pharmaceutically acceptable salts thereof, are present in the pharmaceutical composition in unit dosage form.
In certain embodiments, an effective amount of the pharmaceutical composition is administered to a subject. As used herein, the term "effective amount" refers to an amount sufficient to obtain, or at least partially obtain, a desired effect. For example, a disease-preventing effective amount refers to an amount sufficient to prevent, or delay the onset of disease; a therapeutically effective amount for a disease is an amount sufficient to cure or at least partially arrest the disease and its complications in a patient already suffering from the disease. It is well within the ability of those skilled in the art to determine such effective amounts. For example, an amount effective for therapeutic use will depend on the severity of the disease to be treated, the general state of the patient's own immune system, the general condition of the patient, e.g., age, weight and sex, the mode of administration of the drug, and other treatments administered concurrently, and the like.
In one aspect, the invention relates to the use of any one of the above compounds, pharmaceutically acceptable salts thereof, or a pharmaceutical composition of any one of the above, in the preparation of a medicament targeting the JAK-STAT signaling pathway.
In one aspect, the present invention relates to the use of any one of the above compounds, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of the above, in the manufacture of a medicament for the prevention and/or treatment of a JAK-STAT signaling pathway-associated disease in a subject.
In one aspect, the present invention relates to a method for the prevention and/or treatment of a JAK-STAT signaling pathway-associated disease comprising administering to a subject in need thereof any one of the above compounds, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of the above.
In one aspect, the present invention relates to any one of the compounds described above, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of the above, for use in the prevention and/or treatment of a JAK-STAT signaling pathway-related disease in a subject.
In certain embodiments, the JAK-STAT signaling pathway-associated disease is selected from the group consisting of a tumor, an inflammation, an autoimmune disease, a liver injury, and a nervous system disease.
In certain embodiments, the tumor is selected from pancreatic cancer, brain cancer, colorectal cancer, gastric cancer, liver cancer, lung cancer, ovarian cancer, breast cancer, cervical cancer, lymphoma, human acute promyelocytic leukemia.
In certain embodiments, the inflammatory and autoimmune diseases are selected from chronic inflammation, rheumatoid arthritis, and rheumatoid arthritis.
In certain embodiments, the liver injury is selected from the group consisting of hepatic ischemia reperfusion injury, fatty liver, viral hepatitis, liver fibrosis, and liver failure.
In certain embodiments, the neurological disease is selected from spinal cord injury, subarachnoid hemorrhage, peripheral nerve injury, transverse myelitis, and cerebral infarction.
In certain embodiments, the subject is a mammal, e.g., a bovine, equine, ovine, porcine, canine, feline, rodent, primate; for example, the subject is a human.
In another aspect, the present invention relates to a process for preparing any one of the compounds described above, or a pharmaceutically acceptable salt thereof, comprising the steps of:
(1) preparing a lycopodium cicadae ethanol total extract;
(2) extracting the total ethanol extract of herba Selaginellae Doederleinii with organic solvent (such as petroleum ether and ethyl acetate) to obtain extract;
(3) separating the extracted product by using vacuum liquid chromatography to obtain a primary separated product;
(4) separating the preliminary separation product or one or more fractions thereof by column chromatography and semi-preparative high performance liquid chromatography.
In certain embodiments, step (1) comprises: heating and refluxing the lycopodium cicadae in an ethanol solution, filtering, and removing the solvent in the filtrate to obtain the lycopodium cicadae ethanol total extract.
In certain embodiments, the step (2) comprises: respectively extracting the general ethanol extract of the peperomia pavonica by using petroleum ether and ethyl acetate to obtain three extraction parts, combining the petroleum ether extraction parts and the ethyl acetate extraction parts, and removing the solvent to obtain an extraction product.
In certain embodiments, the step (3) comprises: separating the extracted product by vacuum liquid chromatography (6 × 9cm, 200-300 mesh silica gel, petroleum ether-ethyl acetate 5: 3-0: 1), and detecting by Thin Layer Chromatography (TLC) to obtain primary separated products including 5 parts Fr.A, Fr.B, Fr.C, Fr.D and Fr.E.
In certain embodiments, the step (4) comprises: separating Fr.D by column chromatography (11 × 21cm, GH-ODS silica gel, methanol-water 40: 60-55: 45), and detecting by High Performance Liquid Chromatography (HPLC) to obtain D1, D2, D3 and D4; separation of D2 using semi-preparative HPLC (5X 27cm, YMC-ODS silica gel, methanol-water 45:55) yielded 6 fractions, D2-1, D2-2, D2-3, D2-4, D2-5, D2-6; and respectively separating one or more parts of the D2-1-D2-6 by using semi-preparative HPLC to obtain the compound of the invention.
In certain embodiments, the method further comprises: alkylation or acylation of one compound of the invention to give another compound of the invention.
Advantageous effects
The compound disclosed by the invention can inhibit the activity of a JAK-STAT signal channel in cells, and has good medicinal potential in the aspect of preventing and/or treating diseases (such as tumors, inflammations and autoimmune diseases) related to the JAK-STAT signal channel.
Embodiments of the present invention will be described in detail below with reference to examples and drawings, but those skilled in the art will understand that the following examples and drawings are only illustrative of the present invention and do not limit the scope of the present invention. Various objects and advantageous aspects of the present invention will become apparent to those skilled in the art from the following detailed description of the preferred embodiments.
Drawings
FIG. 1 shows the structural formula of the compound of the present invention.
FIG. 2 shows the results of thin layer chromatography (development conditions: petroleum ether-ethyl acetate 1:3) of the total ethanol extract of Selaginella moellendorfii hieron in example 1, which was separated by column chromatography under reduced pressure.
FIG. 3 shows the results of thin layer chromatography spotting analysis (development conditions: petroleum ether-ethyl acetate 1:3) for reverse phase column chromatography separation on Fr.D in example 1.
FIG. 4 shows the results of thin layer chromatography (development conditions: petroleum ether-acetone 1:2) of the reversed phase column chromatography separation of D3 in example 1.
Detailed Description
It will be appreciated by those skilled in the art that the following examples are illustrative of the invention only and should not be taken as limiting the scope of the invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
In the structural study of the following examples, specific polarimetry was measured using a polarimeter model PolAAr3005 from OA, uk. Positive and negative ion ESI-MS and HR-ESI-MS were measured by an American AB model API 3000 LC MS and an English Micromass model LCT Mass spectrometer, respectively. The circular dichroism spectrum was measured by MOS-450 circular dichroism chromatography, national Biologic Science. NMR spectra were measured using a superconducting NMR spectrometer of JNM-ECA-400 model manufactured by JEOL, Japan, and INOV600 model manufactured by Bruker, USA. Analytical HPLC adopts HP1200 high performance liquid chromatograph, UV detector, and Wondasil as chromatographic columnTMODS column (5 μm,4.6 × 150mm), YMC-PACK-ODS-A column (5 μm,4.6 × 150mm), semi-preparative HPLC using Shimadzu LC-15C type HPLC, SPD-15C detector, and YMC-PACK-ODS-A column (5 μm,10 × 250 mm).
The solvents used in all experiments were of analytical grade and the boiling point range of petroleum ether used was 60-90 ℃.
Example 1: extraction of medicinal material of dindyceps and preparation of compounds 1, 2, 3, 4, 5 and 6
Selaginella cicadae (Peperomia blanda Jacq. Kunth) dried whole grass 1.3kg cut pieces, heated under reflux with 80% (2X 12L) ethanol for 2h, filtered. The obtained filtrates were combined and the solvent was removed under reduced pressure to obtain 290g of the ethanol total extract of Selaginella moellendorfii hieron, which was extracted with petroleum ether (3X 800mL) and ethyl acetate (3X 800mL) to obtain three extraction fractions. Combining the extracted parts of the petroleum ether and the ethyl acetate, removing the solvent under reduced pressure to obtain 105g of a product, separating by reduced pressure column chromatography (VLC, repeated operation for 7 times, 6 multiplied by 9cm, 200-300 mesh silica gel, gradient elution according to the sequence of petroleum ether-ethyl acetate 5:3 → 4:3 → 1:1 → 1:2 → 0:1), and respectively combining the flow parts 1-3 according to the detection result of thin layer chromatography (development condition: petroleum ether-ethyl acetate 1: 3); 4-6; 7-10; 11-13; 14-22 (as shown in fig. 2), and concentrated to obtain 5 fractions (fr.a to fr.e).
Collecting 10g Fr.D, separating by reverse phase column chromatography (11 × 21cm, YMC-ODS silica gel), gradient eluting with methanol-water (40:60,45:55,50:50,55:45), each gradient eluting with 2000ml, collecting fractions, evaporating, performing thin layer chromatography sample application analysis (development condition: petroleum ether-ethyl acetate 1:3), and mixing fractions 1-3 according to chromatography result; 4-6; 7-12; 13-19 (as shown in FIG. 3), to give four fractions D1-D4.
D3 concentrating to small volume, standing, precipitating impurity (30mg), evaporating mother liquor, weighing to 1.4g, separating by reverse phase column chromatography (5 × 27cm, YMC-ODS silica gel, methanol-water 45:55), and combining fractions 12-13 respectively according to detection result of thin layer chromatography (development condition: petroleum ether-acetone 1: 2); 14-15; 16-16 delta; 17-18; 19; 20 (as shown in FIG. 4), six fractions (D3-1 to D3-6) were obtained.
Separation of D3-1 using semi-preparative HPLC (methanol-water 40:60, flow rate 1.5ml/min, pressure 220bar) gave compound 2(2 mg). D3-2 was separated using semi-preparative HPLC (methanol-water 40:60, flow rate 1.5ml/min) to give compound 3(6mg), compound 4(18 mg). D3-3 was separated by gel column chromatography (2X 100cm, methanol) to remove low molecular weight impurities, then separated by semi-preparative HPLC (methanol-water 48:52, flow rate 1.5ml/min, pressure 212bar) to give compound 1(10mg), compound 2, 5 mixture, and further separated by semi-preparative HPLC (acetonitrile-methanol-water 20:23:57, flow rate 1.5ml/min, pressure 180bar) to give compound 2(2mg), compound 5(12 mg). Separation of D3-6 by semi-preparative HPLC (methanol-water 58:42, flow rate 1.5ml/min, pressure 180bar) gave compound 6(5 mg).
The remaining portion of D3-2 was separated by repeated use of semi-preparative HPLC (methanol-water 40:60, flow rate 1.5ml/min, pressure 220bar) several additional times to give 125mg of pure compound 4.
Physicochemical constants and spectral data of Compounds 1-6
Compound 1: white amorphous powder, easily soluble inMethanol;
(c 0.10,MeOH)；(+)HRESI-MS m/z:431.1699[M+H]+,453.1519[M+Na]+(calculated m/z 453.1525); (+) ESI-MS m/z: 431.3[ M + H]+，448.3[M+NH4]+，453.2[M+Na]+，883.5[2M+Na]+；ECD(c 1mM,MeOH)：[θ]213-2450，[θ]2313825，[θ]245-2949，[θ]284+9350；1H NMR(400MHz,CDCl3) (see table 1);13C NMR(100MHz,CDCl3) (see Table 1). NMR data of Compound 1 shown in Table 1 based thereon1H spectrum,13And attributing the results of the full decoupling spectrum of C and the two-dimensional spectra of HSQC, HMBC and the like.
Compound 2: white amorphous powder, readily soluble in methanol;
(c 0.60,MeOH)；(+)HRESI-MS m/z：431.1700[M+H]+(calculated m/z 431.1706); (+) ESI-MS m/z: 431.17[ M + H]+，448.20[M+NH4]+，453.16[M+Na]+；ECD(c 1mM,MeOH)：[θ]213-2120，[θ]231+4253，[θ]243+305，[θ]274.5+9388；1H NMR(400MHz,CDCl3) (see table 1);13C NMR(100MHz,CDCl3) (see Table 1). NMR data of Compound 2 shown in Table 1 based thereon1H spectrum,13And attributing the results of the full decoupling spectrum of C and the two-dimensional spectra of HSQC, HMBC and the like.
TABLE 1 NMR data (400/100MHz, CDCl) for compounds 1, 23)
Compound 3: white amorphous powder, readily soluble in methanol; (+) ESI-MS m/z: 462.5[ M + NH ]4]+，467.5[M+Na]+，483.4[M+K]+；1H NMR(600MHz,CDCl3) (seeTable 2).
Compound 4: white amorphous powder, readily soluble in methanol; (+) ESI-MS m/z: 415.4[ M + H]+，432.4[M+NH4]+，438.4[M+K]+，(-)ESI-MS m/z：413.2[M-H]-；1H NMR(400MHz,CDCl3) (see Table 2).
Compound 5: white amorphous powder, readily soluble in methanol; (+) ESI-MS: m/z 429.3[ M + H ]]+，446.6[M+NH4]+，451.3[M+Na]+，467.3[M+K]+，463.3[M+Cl]-，473.5[M+HCOO]-；1H NMR(400MHz,CDCl3) (see Table 2).
Compound 6: pale yellow solid, readily soluble in chloroform; (+) ESI-MS m/z: 413.2[ M + H]+，430.3[M+NH4]+，435.4[M+Na]+，451.3[M+K]+，847.4[2M+Na]+；1H NMR(400MHz,CDCl3) (see Table 2).
TABLE 2 preparation of compounds 3 to 61H NMR data
And (4) supplementary notes: the determination conditions for Compound 3 were (600MHz, CDCl)3) (ii) a The determination conditions of the compounds 4 to 6 are (400MHz, CDCl)3)。
The structures of compounds 1-6 are respectively as follows:
example 2: derivatization preparation of Compounds 4a to 4f of the invention
Approximately 12mg of the compound 4 prepared in example 1 was weighed, dissolved in 0.5ml of acetone, and 50mg of anhydrous K was added2CO3Mixing, and adding 50 μ l diethyl sulfate dropwise under magnetic stirring at 60 deg.C for ethylation reaction for 6 hr. The reaction product was separated and purified by preparative silica gel thin layer chromatography to give 4a (1.2mg, positive ion ESI-MS m/z:443[M+H]+，459[M+NH4]+)。
approximately 12mg of the compound 4 prepared in example 1 was weighed, dissolved in 0.5ml of acetone, and 50mg of anhydrous K was added2CO3Mixing, adding 50 μ l 1-bromo-3-methyl-2-butene dropwise under magnetic stirring at 60 deg.C, reacting at room temperature for 12H, filtering, washing with a small amount of acetone, mixing filtrates, evaporating under reduced pressure, separating and purifying by preparative silica gel thin layer chromatography to obtain 4b (1.5mg, positive ion ESI-MS M/z: 483[ M + H ] except 3mg of raw material compound 4]+Negative ion ESI-MS m/z: 481[ M-H]-)。
About 12mg of the compound 4 prepared in example 1 was weighed, dissolved in 0.25ml of anhydrous pyridine, quickly added with 0.25ml of acetic anhydride, mixed well, and left to stand for 24 hours in the dark for acetylation. Separating and purifying the reaction product by silica gel thin layer chromatography to obtain 4c (3mg, positive ion ESI-MS M/z: 457[ M + H ]]+Negative ion ESI-MS m/z: 455[ M-H]-)。
About 12mg of the compound 4 prepared in example 1 was weighed, dissolved in 0.25ml of acetone, added with 0.25ml of a 10mg/ml acetone solution of gallic acid, mixed uniformly, added dropwise with 1 drop of 6N hydrochloric acid, mixed uniformly, and left to stand away from light at room temperature for acylation reaction for 7 days. The reaction product was separated and purified by preparative silica gel thin layer chromatography to give 4d (0.8mg, positive ion ESI-MS M/z: 567[ M + H ]]+Negative ion ESI-MS m/z: 565[ M-H]-)。
The compound 4 prepared in example 1 was weighed to about 12mg, dissolved in 0.2ml of anhydrous pyridine, added 13mg of p-nitrobenzoyl chloride rapidly and mixed well, and left to stand in the dark for 10 hours for acylation reaction. The reaction product was separated and purified by preparative silica gel thin layer chromatography to give 4e (3mg, positive ion ESI-MS M/z: 564[ M + H ]]+Negative ion ESI-MS m/z: 562[ M-H]-)。
About 12mg of the compound 4 prepared in example 1 was weighed, dissolved in 0.2ml of anhydrous pyridine, and 8. mu.l of benzoyl chloride was added rapidly and mixed, and left to stand in the dark for 20 hours for acylation reaction. The reaction product was separated and purified by preparative silica gel thin layer chromatography to give 4f (2.2mg, positive ion ESI-MS M/z: 537[ M + H ])]+Negative ion ESI-MS m/z: 535[ M-H]-)。
The structures of compounds 4a-4f are respectively as follows:
example 3: test of JAK-STAT Signal pathway inhibitory Activity of the Compound of formula I of the present invention
Respectively stably transfecting STAT1-Luciferase and STAT3-Luciferase plasmids (taking a-MEM with 10% FBS as a culture medium) by using 4#/HepG2 cells, culturing 4#/HepG2 tumor cells until the logarithmic growth phase, collecting the cells, centrifuging at 1000rpm for 5 minutes, discarding supernatant, suspending by using a proper amount of culture medium, and adjusting the cell concentration to 2 × 105Perml, the cell suspension was inoculated into a 96-well cell culture plate at 100. mu.l per well, and placed in a cell culture chamber (37 ℃, 5% CO)2) In (1). Culturing the cells until the cells are completely attached to the wall, and randomly grouping the cells after the cells grow to the density of 60-70%:
negative control: adding culture medium containing 0.5% final concentration DMSO and having the same volume as the drug to be tested, setting 2 auxiliary holes, respectively adding 11 μ l agonist (IFN- γ or IL-6), and incubating for 5.5 hr;
positive control: three groups of positive controls are set up, 2 auxiliary wells are respectively set, 100 mul of Pyridone 6 with the concentration of 100, 50, 10, 2, 0.4 and 0.08 mul is added into each well, 11 mul of agonist (IFN-gamma or IL-6) is added into each well, and incubation is carried out for 5.5 hours;
and (3) drug treatment: drug treatment groups, each with 2 secondary wells, were added with compounds 1-6, compounds 4a-4f (100. mu.l/well of 250, 100, 50, 10, 2, 0.4, 0.08. mu.M drug) for 1 hour, then with 11. mu.l/well of agonist (IFN-. gamma.or IL-6), and incubated for 5.5 hours;
taking out 96-well plate, carefully sucking, removing culture medium, adding luciferase cell lysis buffer (CCLR)30 μ l per well, shaking gently to fully lyse cells, transferring 20 μ l into enzyme-labeled 96-well plate, adding luciferase substrate 30 μ l, mixing, and placing in enzyme-labeled 96-well plateDetecting fluorescence intensity in the instrument, calculating IC50. IC calculation Using Prism Graphpad5.0 statistical software50The value is obtained. The inhibitory activity results are shown in table 3.
TABLE 3 inhibitory Activity of the inventive Compounds and Positive control JAK inhibitor Pyridone 6 on IFN-. gamma./STAT 1, IL-6/STAT3
As shown in Table 3, Pyridone 6 produces strong inhibition of the IFN-. gamma./STAT 1 signaling pathway and the IL-6/STAT3 signaling pathway, demonstrating successful modeling of cell models. The inhibition activity of 12 compounds of the invention on IFN-gamma/STAT 1, IL-6/STAT3 signaling pathways was tested using a luciferase reporter assay. The 12 compounds of the invention show inhibitory activity to different degrees of IFN-gamma/STAT 1 signal pathway, IC of inhibitory action50Values of 1.35 to 81.47. mu.M; these 12 compounds also showed varying degrees of inhibitory activity on the IL-6/STAT3 signaling pathway, IC of inhibition50A value of 0.59 to>100μM。
The above experimental results show that the compound of the present invention has JAK-STAT signal pathway inhibitory activity, and can be used for preventing and/or treating diseases related to JAK-STAT signal pathway, such as tumors, inflammation, autoimmune diseases, liver injury and nervous system diseases.
While specific embodiments of the invention have been described in detail, those skilled in the art will understand that: various modifications and changes in detail can be made in light of the overall teachings of the disclosure, and such changes are intended to be within the scope of the present invention. The full scope of the invention is given by the appended claims and any equivalents thereof.
Claims (12)
1. Use of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention and/or treatment of a JAK-STAT signaling pathway-associated disease in a subject selected from chronic inflammation, rheumatoid arthritis, liver injury, and spinal cord injury;
the compound has a structure shown in a formula I,
wherein:
R1、R2each selected from the group consisting of hydroxy, methoxy, ethoxy, isopentenyloxy, formyloxy, acetoxy, butyryloxy, isobutyryloxy, benzoyloxy, galloyloxy, p-nitrobenzoyloxy, p-chlorobenzoyloxy, p-fluorobenzoyloxy, or, R1And R2form-O- (CH)2)n-O-, and n ═ 1 or 2;
R3、R4are each selected from C1-3An alkoxy group;
R5、R6are each selected from C1-3Alkoxy, or, R5And R6form-O- (CH)2)n-O-, and n ═ 1 or 2.
2. The use of claim 1, wherein R3、R4Each selected from methoxy, ethoxy, propoxy, isopropoxy.
3. The use of claim 1, wherein R5、R6Each selected from methoxy, ethoxy, propoxy and isopropoxy, or, R5And R6form-O- (CH)2)n-O-, and n ═ 1 or 2.
4. The use of claim 1, wherein the compound satisfies the following condition:
(1)R1-R6not simultaneously being methoxy, and
(2) when R is1、R3、R4Each is methoxy, and R5And R6Formation of-O-CH2when-O-is present, R2Is not a hydroxyl group.
5. The use according to claim 1, wherein,
R1、R2each selected from the group consisting of hydroxy, methoxy, ethoxy, isopentenyloxy, acetoxy, benzoyloxy, galloyloxy, p-nitrobenzoyloxy;
R3、R4each selected from methoxy, ethoxy, propoxy, isopropoxy;
R5、R6each selected from methoxy, ethoxy, propoxy and isopropoxy, or, R5And R6form-O- (CH)2)n-O-, and n ═ 1 or 2;
and, the compound satisfies the following condition:
(1)R1-R6not simultaneously being methoxy, and
(2) when R is1、R3、R4Each is methoxy, and R5And R6Formation of-O-CH2when-O-is present, R2Is not a hydroxyl group.
6. The use according to claim 1, wherein,
R1is hydroxy or methoxy;
R2selected from the group consisting of hydroxy, methoxy, ethoxy, isopentenyloxy, acetoxy, benzoyloxy, galloyloxy, p-nitrobenzoyloxy;
R3、R4、R5、R6each is methoxy; or, R3、R4Each is methoxy, R5And R6Formation of-O-CH2-O-；
And, the compound satisfies the following condition:
(1)R1-R6not simultaneously being methoxy, and
(2) when R is1、R3、R4Each is methoxy, and R5And R6Formation of-O-CH2when-O-is present, R2Is not a hydroxyl group.
7. The use of claim 1, wherein the compound is selected from the group consisting of:
8. the use of claim 1, wherein the pharmaceutical composition further comprises one or more pharmaceutical excipients.
9. The use of claim 1, wherein the liver injury is selected from the group consisting of hepatic ischemia-reperfusion injury, fatty liver, viral hepatitis, liver fibrosis and liver failure.
10. The use of claim 1, wherein the subject is a mammal.
11. The use of claim 1, said subject being selected from the group consisting of bovine, equine, ovine, porcine, canine, feline, rodent, primate.
12. The use of claim 1, wherein the subject is a human.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5981577A (en) * | 1998-06-18 | 1999-11-09 | Development Center For Biotechnology | α-methylene peperomins and halogenated derivatives thereof |
| CN105503786A (en) * | 2015-12-07 | 2016-04-20 | 大连大学 | Secolignan compound-nettle secolignan glucoside E and preparation method thereof |
-
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5981577A (en) * | 1998-06-18 | 1999-11-09 | Development Center For Biotechnology | α-methylene peperomins and halogenated derivatives thereof |
| CN105503786A (en) * | 2015-12-07 | 2016-04-20 | 大连大学 | Secolignan compound-nettle secolignan glucoside E and preparation method thereof |
Non-Patent Citations (5)
| Title |
|---|
| A stereoselective approach to bioactive secolignans: synthesis of peperomin C and its analogues;Darunee Soorukram等;《Tetrahedron》;20140804;第70卷;第7577-7578页，Fig.1，Scheme 2 * |
| Bioactive Compounds from Peperomia pellucida;Su Xu等;《Journal of Natural Products》;20060207;第69卷(第2期);第247页，第249页，Figure 1，Table 1 * |
| Bioactive Secolignans from Peperomia dindygulensis;Jian-lin Wu等;《Journal of Natural Products》;20060407;第69卷(第5期);第790-794页 * |
| Novel secolignans from Peperomia dindygulensis and their inhibitory activities on JAK-STAT signaling pathways;Ruo-Feng Sun等;《Fitoterapia》;20170830;第122卷;第80-84页 * |
| Phosphorylated cyclopropanes in the synthesis of α-alkylidene-γ-butyrolactones: total synthesis of (±)-savinin, (±)-gadain and (±)-peperomin E;Matthew G. Lloyd等;《Organic & Biomolecular Chemistry》;20160823;第14卷;第8971页，Scheme 1 * |
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