CN112125914B - 5-substituted berbamine derivatives, preparation method and application thereof - Google Patents

5-substituted berbamine derivatives, preparation method and application thereof Download PDF

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CN112125914B
CN112125914B CN201910556392.2A CN201910556392A CN112125914B CN 112125914 B CN112125914 B CN 112125914B CN 201910556392 A CN201910556392 A CN 201910556392A CN 112125914 B CN112125914 B CN 112125914B
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berbamine
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姜洪建
徐荣臻
吴水高
徐小尉
陈浩
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Hangzhou Weben Pharmaceuticals Inc
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
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Abstract

The invention relates to berberine derivatives of a general formula I or pharmaceutically acceptable salts thereof, a method for preparing the compounds, a pharmaceutical composition containing the compounds and application of the compounds in preparing antitumor drugs.

Description

5-substituted berbamine derivatives, preparation method and application thereof
Technical Field
The invention belongs to the fields of natural medicines and medicinal chemistry, and relates to novel 5-substituted berberine derivatives, a method for preparing the compounds, a composition containing the compounds and application of the compounds in preparing antitumor medicines.
Background
Berbamine (BBM) is a dibenzyl isoquinoline alkaloid extracted from Chinese herbal medicine Berberine.
Berbamine has effects of stimulating proliferation of marrow cells, increasing content of hematopoietic stem cell colony factor (GCSF), promoting proliferation of bone marrow hematopoietic stem cells and granulocyte progenitor cells, differentiating into granulocyte, and promoting proliferation of leukocyte (Lin Chuanrong, etc., chinese patent medicine (1994, 16 (7): 29) for clinical observation of treating chemotherapy leukopenia by treating leukopenia with lifting gelatin (berbamine).
The berbamine has an inhibiting effect on cytotoxic T lymphocytes, has an obvious promoting effect on the activity of natural killer cells of mice in vitro, can induce high-level interleukin II (IL-2) in vivo and in vitro, and can avoid toxic and side effects caused by treating tumors with large doses of IL-2. Experiments prove that the berberine has good protective effect on the immune system of radiation damaged mice (Liu Xin and the like, the immunomodulatory effect of the berberine on BALB/C mice, the journal of Chinese medical science, 1996, 25 (3): 229; luo Chongnian and the like, the inhibitory effect of the berberine on the activity of spleen cytotoxic T lymphocytes of the mice, the journal of Chinese pharmacology and toxicology, 1995,9 (2): 159-160; ge Mingzhu and the like, the experimental study of the immune protective effect of the berberine hydrochloride on the radiation mice, the journal of immunology, 1998,14 (4): 238).
The Chinese has approved the marketing of berbamine hydrochloride tablets for treating leukopenia caused by various reasons, including preventing leucopenia after cancer radiotherapy and chemotherapy. The inhibition of cell proliferation by berbamine, such as the obvious inhibition of brain glioblastoma cells, human cervical cancer cells, ascites cancer cells and melanoma cells by berbamine and its derivatives (Zhang Jingong, etc., the influence of the structure of berbamine and its derivatives on the growth and proliferation of cervical cancer (CHeLa) cells, university of south-open university (Nature science), 1996,29 (2): 89; zhang Jingong, etc., the influence of berbamine and its derivatives on the proliferation of malignant melanoma cells, chinese herbal medicines, 1997, 28 (8): 483; zhang Jingong, etc., the initial detection of antitumor effect in vivo by berbamine derivatives (EBB), chinese herbal medicines, 1998,29 (4): 243; duan Jiangyan, etc., the influence of berbamine compounds on the calmodulin level in melanoma cells, chinese herbal medicines, 2002,33 (1): 59) have also been reported. Wherein [ O- (4-ethoxy) -butyl]Berberine (EBB) is a highly specific CaM antagonist with a specificity factor of 6.5 times higher than that of berbamine. EBB induces apoptosis in lung cancer cells while maintaining normal biological functions of major organ cells (Duan Jiangyan et al, [ O- (4-ethoxy) -butyl ]]Primary detection of berbamine-induced apoptosis in lung cancer, university of shanxi university (natural science edition), 2001, 15 (4): 55). Another berbamine derivative is O-Dansyl Berbamine (DB), which contains a hydrophobic fluorescent group. DB pairs CaM-dependent erythrocyte membrane Ca 2+ +Mg 2+ ATPase has 25 times stronger inhibitory activity than berbamine; DB has obvious inhibition effect on the activity of granzyme phosphodiesterase in cells, and the relation between dosage and activity exists. In addition, DB has been found to have a stronger effect on lung cancer cells than berbamine, but less cytotoxicity on human embryonic lung cells, and its inhibition of lung cancer cells is associated with the inhibition of oncogenes, as well as with the control of inactivated oncogenes (Zhang Jingong et al, the effect of the calmodulin antagonist O-dansyl berbamine on phosphodiesterase and the proliferation of lung cells, university of south-open, university journal of Nature, 200l,34 (3): 64).
Some berbamine derivatives have been reported to be synthesized and show a certain antitumor activity in vitro (European Journal of Medicinal Chemistry 2012,54,867;European Journal of Medicinal Chemistry 2009,44,3293), but no animal efficacy data has been published yet. Studies have shown that the small molecule compound berbamine has significant anti-human leukemia effect (Leukemia Research 2006,30, 17), but the amount of drug required to achieve anti-leukemia and anti-tumor effects is large.
It is therefore necessary to synthesize and develop new berbamine derivatives having better antitumor activity.
Disclosure of Invention
The invention aims at providing a berbamine derivative shown in a general formula (I) or a pharmaceutically acceptable salt thereof.
Wherein n=0-15;
w is selected from H and methylene;
x is selected from nitrogen or is absent;
R 1 、R 2 each independently selected from H, C 1 -C 10 An alkyl group; or R is 1 、R 2 With X to form a substituted or unsubstituted C 3 -C 7 A heterocyclic group; or R is 1 And R is 2 Is absent; the heterocyclic group contains at least one nitrogen and optionally further heteroatoms such as oxygen or sulfur; wherein said substitution is selected fromGroup substitution: halogen, amino, hydroxy, C 1 -C 6 One or more of the alkyl groups.
Y is selected from O, S or absent;
z is selected from H, R 5 SO 2 Or R is 6 Wherein R is 5 Or R is 6 Each independently selected from the group consisting of substituted or unsubstituted phenyl, naphthyl and C 5 -C 10 Heteroaryl, wherein said substitution means substitution with a group selected from the group consisting of: halogen, amino, hydroxy, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 One or more of alkoxy groups;
R 3 、R 4 each independently selected from H, halogen, amino, hydroxy, C 1 -C 10 An alkyl group;
provided that the conditions are that,
when W is selected from H, R 1 -X-R 2 Absence of;
when n=0, Y is absent and Z is selected from H or R 5 SO 2 ；
When n=1 to 15, Z is selected from R 6 ；
When n=0, y is absent and Z is selected from H, W is selected from methylene.
In a preferred embodiment, the present invention provides a berbamine derivative represented by the general formula (I-A) or a pharmaceutically acceptable salt thereof,
wherein n, Y, Z, R 3 And R is 4 Is as defined in formula (I); provided that when n=0, Y is absent and Z is selected from R 5 SO 2 The method comprises the steps of carrying out a first treatment on the surface of the When n=1 to 15, Z is selected from R 6 。
In a preferred embodiment, the present invention provides a berbamine derivative represented by the general formula (I-B) or a pharmaceutically acceptable salt thereof,
wherein R is 1 、R 2 Each independently selected from H, C 1 -C 10 Alkyl, or R 1 、R 2 Form a substituted or unsubstituted C with N 3 -C 7 A heterocyclic group; the heterocyclic group contains at least one nitrogen and optionally further heteroatoms such as oxygen or sulfur; wherein the substituents are selected from halogen, amino, hydroxy, C 1 -C 6 One or more of alkyl groups; n, Y, Z, R 3 And R is 4 Is as defined in formula (I); provided that when n=0, Y is absent and Z is selected from H or R 5 SO 2 The method comprises the steps of carrying out a first treatment on the surface of the When n=1 to 15, Z is selected from R 6 。
In a preferred embodiment, the present invention provides a berbamine derivative represented by the general formula (I-C) or a pharmaceutically acceptable salt thereof,
wherein n=1-15; z is selected from R 6 ；R 3 、R 4 And R is 6 Is as defined in formula (I).
In a preferred embodiment, the present invention provides a berbamine derivative represented by the general formula (I-D) or a pharmaceutically acceptable salt thereof,
wherein R is 5 Is as defined in formula (I).
In a preferred embodiment, the present invention provides a berbamine derivative represented by the general formula (I-E) or a pharmaceutically acceptable salt thereof,
wherein R is 1 、R 2 Each independently selected from H, C 1 -C 10 Alkyl, or R 1 、R 2 Form a substituted or unsubstituted C with N 3 -C 7 A heterocyclic group; the heterocyclic group contains at least one nitrogen and optionally further heteroatoms such as oxygen or sulfur; wherein the substituents are selected from halogen, amino, hydroxy, C 1 -C 6 One or more of alkyl groups; n=1 to 15; z is selected from R 6 ；R 3 、R 4 And R is 6 Is as defined in formula (I).
In a preferred embodiment, the present invention provides a berbamine derivative represented by the general formula (I-F) or a pharmaceutically acceptable salt thereof,
wherein R is 1 、R 2 Each independently selected from H, C 1 -C 10 Alkyl, or R 1 、R 2 Form a substituted or unsubstituted C with N 3 -C 7 A heterocyclic group; the heterocyclic group contains at least one nitrogen and optionally further heteroatoms such as oxygen or sulfur; wherein the substituents are selected from halogen, amino, hydroxy, C 1 -C 6 One or more of alkyl groups; r is R 5 Is as defined in formula (I).
In a preferred embodiment, the present invention provides a berbamine derivative represented by the general formula (I-G) or a pharmaceutically acceptable salt thereof,
wherein R is 1 、R 2 Each independently selected from H, C 1 -C 10 Alkyl, or R 1 、R 2 Form a substituted or unsubstituted C with N 3 -C 7 A heterocyclic group; the heterocyclic group contains at least one nitrogen and optionally further heteroatoms such as oxygen or sulfur; wherein the substitution refers to substitution with a group selected from the group consisting of: halogen, amino, hydroxy, C 1 -C 6 Alkyl groupOne or more of the following.
In a preferred embodiment, the present invention provides the following compounds, or pharmaceutically acceptable salts thereof:
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it is a further object of the present invention to provide a process for preparing the berbamine derivatives of formula (I) according to the invention.
The method comprises the following steps:
step one: reacting compound (II) (Y is selected from sulfur or oxygen) with hydroxyl-protected bromoor iodoalcohol (III) under alkaline conditions to obtain compound (IV). Wherein PG is a protecting group (including but not limited to TBS, DPS, THP, etc.). The selection of protecting groups can be found in Greene's Protective Groups in Organic Synthesis (4 th Ed.) Hoboken, new Jersey: john Wiley & Sons, inc. The solvent used in the reaction includes aprotic polar solvents such as Tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), dimethylformamide (DMF), or the like. The reaction temperature of the reaction is generally from 0 to 80℃and generally varies depending on the reaction raw materials used and the base. The base used in the reaction may be a metal hydride such as sodium hydride, potassium hydride; metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, aluminum hydroxide, barium hydroxide, and calcium hydroxide; metal carbonates such as sodium carbonate, potassium carbonate, magnesium carbonate, cesium carbonate; metal acid carbonates such as sodium bicarbonate; organic amines such as ammonium hydroxide, triethylamine, diisopropylethylamine, DBN, DBU, and the like.
Step two: the resulting compound (IV) is deprotected (e.g., under TBAF or acidic conditions) and then contacted with an activating reagent (e.g., tsCl, msCl or Tf 2 (O)) to give the compound (V). LG is a leaving group (e.g., ts, ms, tf)
Step three: the berbamine (BBM, commercially available) is reacted with the compound (V) under alkaline conditions to give the berbamine derivative (I-A). Wherein the base used is referred to in step one.
Step four: the berberine derivative (I-A) is reacted with formaldehyde and hydrochloric acid in the presence of zinc dichloride to produce 5-chloromethyl berberine derivative (I-A'). Experimental operation was performed according to the well established operating conditions in the art, see (G.Blanc, bull.Soc.Chim.France (4), 313 (1923); R.C.Fuson, C.H.McKeever, org.React.1,63 (1942)).
Step five: reacting a berbamine derivative (I-A') with R under alkaline conditions 1 R 2 NH reacts to generate 5-substituted berberine derivative shown in general formula (I-B). Wherein the base used is referred to in step one.
Wherein n=1 to 15, r 1 、R 2 、R 3 、R 4 Y, Z and X are as defined above for formula (I).
The second method is as follows:
step one: berberine (BBM) and sulfonyl chloride R 5 SO 2 Cl in alkaline barObtaining a compound (I-D) through reaction under the reaction piece; the base used in the reaction may be a metal hydride such as sodium hydride, potassium hydride; metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, aluminum hydroxide, barium hydroxide, and calcium hydroxide; metal carbonates such as sodium carbonate, potassium carbonate, magnesium carbonate, cesium carbonate; metal acid carbonates such as sodium bicarbonate; organic amines such as ammonium hydroxide, triethylamine, diisopropylethylamine, DBN, DBU, and the like; solvents used for the reaction include DCM, THF, DMSO, DMF and the like; the reaction temperature of the reaction is generally 0 to 80 ℃, and generally varies with the different reaction raw materials and alkali used;
step two: the berberine derivative (I-D) is reacted with formaldehyde and hydrochloric acid in the presence of zinc dichloride to produce 5-chloromethyl berberine derivative (I-D'). Experimental operation was performed according to the well established operating conditions in the art, see (G.Blanc, bull.Soc.Chim.France (4), 313 (1923); R.C.Fuson, C.H.McKeever, org.React.1,63 (1942)).
Step three: reacting a berbamine derivative (I-D') with R under alkaline conditions 1 R 2 NH reacts to produce 5-substituted berberine derivative shown in general formula (I-F). Wherein the base used is referred to in step one.
Step four: under alkaline conditions, the 5-substituted berberine derivative shown in the general formula (I-F) undergoes hydrolysis reaction to generate the berberine derivative shown in the general formula (I-H).
R 1 、R 2 、R 5 And X is as defined above for formula (I).
Conventional chemical transformations may be used to practice the present invention. Those skilled in the art can determine the appropriate chemical reagents, solvents, protecting groups and reaction conditions for these chemical transformations. Relevant information is described in r.larock, comprehensive Organic Transformations, VCH publishers (1989); t.w.greene and p.g.m.wuts, protective Groups in Organic Synthesis, 3 rd edition, john Wiley and Sons (1999); fieser and M.Fieser, fieser and Fieser's Reagents for Organic Synthesis, john Wiley and Sons (1994); and Encyclopedia of Reagents for Organic Synthesis, john Wiley and Sons (1995) edited by l.paquette and later versions thereof.
It is a further object of the present invention to provide the use of a compound of the present invention or a pharmaceutical composition comprising the compound for the manufacture of a medicament, in particular an antitumor medicament. Accordingly, the present invention provides a method of treating a patient having a tumor comprising administering to a patient in need of treatment a therapeutically effective amount of at least one compound of the present invention. The tumor is selected from leukemia, multiple myeloma, lymphoma, liver cancer, gastric cancer, breast cancer, cholangiocellular carcinoma, pancreatic cancer, lung cancer, carcinoma of large intestine, osteosarcoma, melanoma, human cervical cancer, glioma, nasopharyngeal carcinoma, laryngeal carcinoma, esophageal carcinoma, middle ear tumor, prostate cancer, etc.
The pharmaceutical formulations of the present invention are manufactured in known ways, including conventional mixing, dissolving or lyophilizing processes. The compounds of the invention may be formulated into pharmaceutical compositions and administered to a patient by a variety of routes suitable for the chosen mode of administration, such as orally or parenterally (via intravenous, intramuscular, topical or subcutaneous routes).
Thus, the compounds of the invention may be administered systemically, e.g., orally, in combination with a pharmaceutically acceptable carrier, such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules and may be compressed into tablets. For oral therapeutic administration, the active compounds may be combined with one or more excipients and used in the form of swallowable tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers and the like. Such compositions and formulations should contain at least 0.1% active compound. The proportions of such compositions and formulations may, of course, vary and may comprise from about 1% to about 99% by weight of a given unit dosage form. In such therapeutically useful compositions, the amount of active compound is such that an effective dosage level is obtained.
Tablets, troches, pills, capsules and the like may also contain: binders, such as gum tragacanth, acacia, corn starch or gelatin; excipients, such as dicalcium phosphate; disintegrants such as corn starch, potato starch, alginic acid and the like; lubricants, such as magnesium stearate; and sweeteners such as sucrose, fructose, lactose or aspartame; or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as vegetable oil or polyethylene glycol. Various other materials may be present as coatings or to otherwise alter the physical form of the solid unit dosage form. For example, tablets, pills, or capsules may be coated with gelatin, waxes, shellac, or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl or propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used to prepare any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amount employed. In addition, the active compounds may be incorporated into sustained release formulations and sustained release devices.
The active compounds can also be administered intravenously or intraperitoneally by infusion or injection. An aqueous solution of the active compound or salt thereof may be prepared, optionally mixed with a non-toxic surfactant. Dispersants in glycerol, liquid polyethylene glycols, triacetin and mixtures thereof and oils can also be prepared. Under ordinary conditions of storage and use, these formulations contain a preservative to prevent microbial growth.
Pharmaceutical dosage forms suitable for injection or infusion may comprise sterile aqueous solutions or dispersions or sterile powders of the active ingredient (optionally encapsulated in liposomes) in immediate formulations containing solutions or dispersions suitable for sterile injectable or infusible. In all cases, the final dosage form must be sterile, liquid and stable under the conditions of manufacture and storage. The liquid carrier may be a solvent or liquid dispersion medium including, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, and the like), vegetable oils, non-toxic glycerides, and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions, or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like). In many cases, it is preferable to include isotonic agents, for example, sugars, buffers, or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use of compositions (e.g., aluminum monostearate and gelatin) with a delayed absorption agent.
Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient present in a previously sterile-filtered solution thereof.
Useful solid carriers include crushed solids (e.g., talc, clay, microcrystalline cellulose, silica, alumina, etc.). Useful liquid carriers include water, ethanol or ethylene glycol or water-ethanol/ethylene glycol mixtures in which the compounds of the present invention may be dissolved or dispersed, optionally with the aid of non-toxic surfactants, in effective amounts. Adjuvants (e.g., fragrances) and additional antimicrobial agents may be added to optimize properties for a given use.
Thickeners (e.g., synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses, or modified inorganic materials) can also be used with the liquid carrier to form coatable pastes, gels, ointments, soaps, and the like, for direct application to the skin of a user.
The therapeutic requirements of a compound or an active salt or derivative thereof depend not only on the particular salt selected, but also on the mode of administration, the nature of the disease to be treated and the age and condition of the patient, ultimately on the discretion of the attendant physician or clinician.
The above formulations may be presented in unit dosage forms which are physically discrete units containing a unit dose suitable for administration to the human and other mammalian bodies. The unit dosage form may be a capsule or tablet, or many capsules or tablets. The amount of unit dose of the active ingredient may vary or be adjusted from about 0.1 to about 1000 milligrams or more, depending on the particular treatment involved.
The present invention relates to pharmaceutically acceptable salts of the compounds of formula (I) of the present invention.
As used herein, the term "C 1 -C 10 Alkyl "refers to straight or branched, substituted or unsubstituted alkyl groups containing from 1 to 10 carbon atoms. C (C) 1 -C 10 Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, t-butyl, n-pentyl, n-hexyl, and n-dodecyl.
The term "aryl" refers to aromatic hydrocarbon groups without heteroatoms, including aryl, aralkyl, and alkylaryl groups. "aryl" as described herein is preferably C 6 -C 18 Aryl, more preferably C 6 -C 12 Aryl, most preferably phenyl and naphthyl.
The term "heterocyclyl" refers to a non-aromatic hydrocarbon radical containing a heterocyclic atom. Heteroatoms refer to nitrogen, oxygen or sulfur. The heterocyclyl may contain one or more heteroatoms. "heterocyclyl" as described herein is preferably C 5 -C 18 Heterocyclyl, more preferably C 5 -C 10 Heterocyclyl, most preferably pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 2, 3-indolinyl, 1,2,3, 4-tetrahydroquinolinyl, tetrahydroimidazolyl, tetrahydropyrazolyl, triazinyl, and the like;
the term "heteroaryl" refers to aromatic hydrocarbon groups containing heteroatoms, including heteroaryl, heteroaralkyl, and alkylheteroaryl. Heteroatoms refer to nitrogen, oxygen or sulfur. Heteroaryl groups may contain one or more heteroatoms. "heteroaryl" as described herein is preferably C 5 -C 18 Heteroaryl, more preferably C 5 -C 10 Heteroaryl, most preferably pyridyl, furyl, benzo [1,3 ]]Dioxolane (dioxy), benzo [1,4]Dioxinyl (dioxanyl), thienyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, thiadiazolyl, isoquinolinyl, indazolyl, benzoxazolyl, benzofuranyl, indolizinyl (indopyridyl), imidazopyridinyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolylDiazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyridinyl, quinazolinyl, purinyl, pyrrolo [2,3 ]]Pyrimidinyl pyrazolo [3,4 ]]Pyrimidinyl and benzo (b) thienyl, 3H-thiazolo [2,3-c ]][l,2,4]Thiadiazolyl, imidazo [ l,2-d]-l,2, 4-thiadiazolyl, imidazo [2, l-b]-l,3, 4-thiadiazolyl, lH, 2H-furo [3,4-d ]]-1,2, 3-thiadiazolyl, lH-pyrazolo [5,l-c]-l,2, 4-triazolyl, pyrrolo [3,4-d]-l,2, 3-triazolyl, cyclopentatriazolyl, 3H-pyrrolo [3,4-c]Isoxazolyl, lH, 3H-pyrrolo [ l,2-c]Oxazolyl, pyrrolo [2, l-b]Oxazolyl group and the like
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
As used herein, examples of the term "pharmaceutically acceptable salts of the compounds of formula (I)" are organic acid salts formed from organic acids forming pharmaceutically acceptable anions; these organic acid salts include, but are not limited to, tosylate, mesylate, malate, acetate, triacetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, alpha-ketoglutarate, and alpha-glycerophosphate; suitable inorganic salts may also be formed; such inorganic acid salts include, but are not limited to, hydrochloride, sulfate, nitrate, carbonate, phosphate, hydrobromide, hydroiodide, and the like.
Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art. For example, by reacting a sufficient amount of a basic compound with a suitable acid that provides a pharmaceutically acceptable anion.
"protecting groups" refer to those groups that once attached to an active moiety (e.g., hydroxyl or amino) prevent interference of such moiety by subsequent reactions and may be removed by conventional means after the reaction. Examples of hydroxyl protecting groups include, but are not limited to, alkyl, benzyl, allyl, trityl (i.e., triphenylmethyl), acyl (e.g., benzoyl or acetyl), silyl (e.g., trimethylsilyl, triethylsilyl, and t-butyldimethylsilyl), alkoxycarbonyl, aminocarbonyl (e.g., dimethylaminocarbonyl, methylethylaminocarbonyl, and phenylaminocarbonyl), alkoxymethyl, benzyloxymethyl, and alkylmercaptomethyl. Examples of amino protecting groups include, but are not limited to, alkoxycarbonyl, alkanoyl, aryloxycarbonyl, aryl-substituted alkyl, and the like. Hydroxy and amino protecting groups have been discussed in t.w. greene and p.g. m.wuts, protective Groups in Organic Synthesis, 2 nd edition, john Wiley and Sons (1991). Both the hydroxyl and amino protecting groups can be removed after the reaction by conventional methods. Leaving groups refer to groups that are substituted in a nucleophilic reaction with other nucleophiles, including, but not limited to: halogen (Cl, br, I), ts, ms, and Tf.
The two chiral centers of the berbamine derivative have a stereochemical structure shown in a structural formula (I). Definition and definition of stereochemistry as used herein generally follows MCGRAW-HILL DICTIONARY OF CHEMICAL TERMS (s.p. parker, ed., MCGRAW-Hill Book Company, new York, 1984); ELIEL, E.and WILEN, S., STEREOCHEMISTRY OF ORGANIC COMPOUNDS (John Wiley & Sons, inc., new York, 1994). Many organic compounds exist in optically active form, i.e. they have the ability to rotate the plane of plane polarization.
The term "treatment" as used herein generally refers to obtaining a desired pharmacological and/or physiological effect. The effect may be prophylactic according to the prevention of the disease or symptoms thereof, in whole or in part; and/or may be therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the disease. As used herein, "treatment" encompasses any treatment of a disease in a patient, including: (a) Preventing diseases or symptoms which occur in patients who are susceptible to the diseases or symptoms but are not yet diagnosed with the disease; (b) inhibiting the symptoms of the disease, i.e., arresting its development; or (c) alleviating a symptom of the disease, i.e., causing regression of the disease or symptom.
In the present application, unless specifically defined, the abbreviations used have the meanings indicated below:
min refers to minutes;
h means hours;
d refers to the day;
DEG C refers to degrees Celsius;
BBM refers to berbamine;
ts refers to p-toluenesulfonyl;
ms is nail sulfonyl;
tf means trifluoromethanesulfonyl;
TsCl refers to p-toluenesulfonyl chloride;
DPS refers to tert-butyldiphenylsilyl;
TBAF refers to tetrabutylammonium fluoride;
TBS means t-butyldimethylsilyl;
TEA refers to triethylamine;
THP refers to tetrahydropyranyl;
PG refers to a protecting group;
LG is a leaving group;
NaH refers to sodium hydride;
KOH refers to potassium hydroxide;
TLC refers to thin layer chromatography;
mmol refers to millimoles;
mL refers to milliliters;
l is L;
m refers to concentration unit mol/L;
mM refers to concentration units millimoles/liter;
mu M refers to concentration units in micromoles per liter;
me means methyl;
ac refers to acetyl;
DCM refers to dichloromethane;
THF refers to tetrahydrofuran;
DMF refers to N, N-dimethylformamide;
DMSO refers to dimethyl sulfoxide;
DIPEA means N, N-diisopropylethylamine;
LC-MS refers to the use of liquid chromatography with mass spectrometry;
the present application also includes isotopically-labeled compounds identical to those recited herein, but for the replacement of one or more atoms by an atom having an atomic weight or mass number different from the atomic weight or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present application include hydrogen, carbon, nitrogen, oxygen, phosphorusIsotopes of sulfur, fluorine, iodine and chlorine, such as respectively 2 H、 3 H、 11 C、 13 C、 14 C、 13 N、 15 N、 15 O、 17 O、 18 O、 31 P、 32 P、 35 S、 18 F、 123 I、 125 I and 36 cl, and the like. Certain isotopically-labeled compounds of the present application (e.g., with 3 H is H 14 C-labeled) can be used in compound and/or substrate tissue distribution analysis. Tritiation (i.e 3 H) And carbon-14 (i.e 14 C) Isotopes are particularly preferred for their ease of preparation and detectability. Isotopically-labeled compounds of the present application can generally be prepared by following procedures analogous to those disclosed in the schemes and/or examples below by substituting an isotopically-labeled reagent for an non-isotopically-labeled reagent. In addition, the use of heavier isotopes (such as deuterium (i.e. 2 H) Substitution may provide certain therapeutic advantages resulting from higher metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), and thus may be preferred in certain circumstances, where deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is substituted with at least one deuterium.
Detailed Description
The present invention relates to 5-substituted berbamine derivatives of general formula (I) or pharmaceutically acceptable salts thereof. The present invention is described in detail by the following examples, which are not meant to be limiting in any way. The foregoing has described the invention in detail, and embodiments thereof have been disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the invention without departing from the scope of the invention.
Example 1: synthesis of Compound 1
0.5g (5.26 mmol) of 3-hydroxypyridine was dissolved in DMSO (5 mL), 2g (6.14 mmol) of cesium carbonate and 1.33g (5.26 mmol) of 3-bromopropyl tert-butyldimethylsilyl ether were added, and the mixture was heated to 80℃and reacted for 16 hours. After the completion of the reaction, the reaction mixture was quenched with water, extracted with DCM, the organic phases were combined, dried over saturated brine, concentrated under reduced pressure, and the crude product obtained was isolated as an oily compound (310 mg, 22%) by column chromatography.
The oily compound (310 mg,1.16 mmol) was dissolved in MeOH (3 mL), concentrated hydrochloric acid (0.3 mL) was added, and the reaction was stirred at 40℃for 1h. After the reaction, the reaction solution was concentrated at a temperature of less than 40℃under reduced pressure, pyridine (3 mL) was added for dissolution, the temperature was lowered to 0-5℃and p-TsCl (240 mg,1.26 mmol) was added, the temperature was raised to 25-30℃and the reaction was stirred for 2 hours. After the completion of the reaction, the reaction mixture was quenched with water, extracted with DCM, the organic phases were combined, dried over saturated brine, concentrated under reduced pressure, and the crude product obtained was isolated as a yellow solid (280 mg, 78.5%) by column chromatography.
Berberine hydrochloride (BBM, 500mg,0.73 mmol) was dissolved in DMF (5 mL), cooled to 0-5 ℃, naH (95 mg,2.38 mmol) was added, stirred for 30min at constant temperature, the above solid compound (240 mg,0.78 mmol) was added, and the temperature was raised to 40℃and stirred for 2h. After the completion of the reaction, the reaction mixture was quenched with water, extracted with DCM, the organic phases were combined, dried over saturated brine, and concentrated under reduced pressure, and the crude product obtained was separated by column chromatography to give compound 1 (250 mg, 45.8%) as a white solid.
LC-MS:m/z 745.3(M+H),372.7(1/2M+H). 1 H NMR(400MHz,CDCl 3 )δ8.33(d,J＝2.8Hz,1H),8.21(dd,J＝4.4,1.5Hz,1H),7.26–7.15(m,3H),7.09(d,J＝8.3Hz,1H),6.87(d,J＝8.0Hz,1H),6.79(s,1H),6.62(d,J＝8.0Hz,1H),6.55(s,1H),6.42(s,2H),6.30(s,1H),5.99(s,1H),4.29(q,J＝5.8Hz,4H),3.86(s,2H),3.77(s,3H),3.63(s,3H),3.42(s,2H),3.24(s,2H),3.14(s,3H),3.04(d,J＝14.1Hz,1H),2.93(d,J＝9.0Hz,1H),2.84(s,6H),2.60(s,3H),2.36(p,J＝6.0Hz,2H),2.26(d,J＝11.4Hz,3H).
Example 2: synthesis of Compound 2
Prepared as in example 1, starting with 4-hydroxypyridine and BBM (500 mg,0.73 mmol) to afford compound 2 (270 mg, 49.5%) as a white solid.
LC-MS:m/z 745.3(M+H),372.7(1/2M+H). 1 H NMR(400MHz,CDCl 3 )δ8.46–8.37(m,2H),7.26(d,1H),7.08(d,1H),6.90–6.76(m,4H),6.61(d,J＝8.7Hz,1H),6.55(s,1H),6.42(s,2H),6.30(s,1H),5.99(s,1H),4.28(dt,J＝7.9,6.1Hz,4H),3.87(s,2H),3.77(s,3H),3.63(s,3H),3.43(s,2H),3.27(dd,J＝13.6,6.4Hz,2H),3.14(s,3H),3.05(d,J＝11.8Hz,1H),3.01–2.91(m,2H),2.86(d,J＝16.3Hz,5H),2.60(s,3H),2.43–2.29(m,2H),2.28(s,3H).
Example 3: synthesis of Compound 3
Prepared as in example 1, starting with 2-trifluoromethyl-5-hydroxypyridine and BBM (400 mg,0.59 mmol) to give compound 3 (280 mg, 58.8%) as a white solid.
LC-MS:m/z 813.3(M+H),406.8(1/2M+H). 1 H NMR(400MHz,CDCl 3 )δ8.38(d,J＝2.8Hz,1H),7.56(d,J＝8.8Hz,1H),7.33–7.23(m,3H),7.04(d,J＝8.5Hz,1H),6.87(d,J＝8.1Hz,1H),6.78(d,J＝7.9Hz,1H),6.62–6.52(m,2H),6.39(s,1H),6.30(s,1H),5.98(s,1H),4.36(t,J＝6.0Hz,2H),4.29(t,J＝5.9Hz,2H),3.83(d,J＝10.5Hz,2H),3.77(s,3H),3.62(s,3H),3.41(s,2H),3.24(dd,J＝13.0,6.4Hz,2H),3.14(s,3H),3.08–2.99(m,1H),2.99–2.80(m,2H),2.83(s,5H),2.59(s,3H),2.37(q,J＝5.8Hz,2H),2.26(s,3H).
Example 4: synthesis of Compound 4
Prepared as in example 1, starting with 2-methoxy-5-hydroxypyridine and BBM (500 mg,0.73 mmol) to give compound 4 (350 mg, 61.6%) as a white solid.
LC-MS:m/z 775.3(M+H),387.7(1/2M+H).1H NMR(400MHz,CDCl 3 )δ7.83(d,J＝3.0Hz,1H),7.23m,2H),7.09(d,J＝8.3Hz,1H),6.87(d,J＝8.1Hz,1H),6.79(s,1H),6.65(dd,J＝13.5,8.6Hz,2H),6.55(s,1H),6.42(s,2H),6.30(s,1H),6.00(s,1H),4.25(dt,J＝29.0,6.1Hz,4H),3.90(s,3H),3.86(s,2H),3.77(s,3H),3.63(s,3H),3.43(m,2H),3.24(m,2H),3.15(s,3H),3.03(d,J＝14.2Hz,1H),2.93(d,J＝9.3Hz,1H),2.84(s,6H),2.60(s,3H),2.37–2.20(m,5H).
Example 5: synthesis of Compound 5
Prepared as in example 1, starting with phenol and BBM (500 mg,0.73 mmol) to afford compound 5 (400.0 mg, 73.4%) as a white solid.
LC-MS:m/z 743.3(M+1). 1 H NMR(400MHz,CDCl 3 )7.32–7.23(m,4H),7.10(d,J＝8.2Hz,1H),6.99–6.84(m,3H),6.79(s,1H),6.64(d,J＝8.2Hz,1H),6.55(s,1H),6.43(s,2H),6.30(s,1H),6.00(s,1H),4.29(t,J＝6.2Hz,2H),4.24(t,J＝6.3Hz,2H),3.86(m,2H)，3.78(s,3H),3.63(s,3H),3.45(m,2H),3.30-3.20(m,2H),3.15(s,3H),3.0-2.80(m,8H),2.59(s,3H),2.34(m,2H),2.28(s,3H).
Example 6: synthesis of Compound 6
Prepared as in example 1 starting with 3-fluorophenol and BBM (500 mg,0.73 mmol) to give compound 6 (390.0 mg, 69.8%) as a white solid
LC-MS:m/z 761.3(M+1). 1 H NMR(400MHz,CDCl 3 )δ7.29(dd,J＝8.3,2.0Hz,1H),7.20(td,J＝8.6,6.8Hz,1H),7.09(dd,J＝8.3,2.5Hz,1H),6.86(d,J＝8.1Hz,1H),6.78(dd,J＝8.0,2.0Hz,1H),6.71(dd,J＝8.1,2.2Hz,1H),6.69–6.60(m,3H),6.55(s,1H),6.43(s,2H),6.30(s,1H),6.00(s,1H),4.28(t,J＝6.1Hz,2H),4.21(t,J＝6.1Hz,2H),3.85(d,J＝9.3Hz,2H),3.77(s,3H),,3.63(s,3H),3.42(m,2H),3.30-3.20(m,2H),3.14(s,3H),3.0-2.80(m,8H),2.62-2.54(m,3H),2.44-2.33(m,2H),2.27(s,3H).
Example 7: synthesis of Compound 7
Prepared as in example 1 starting with 3-methoxyphenol and BBM (500 mg,0.73 mmol) to give compound 7 (410.0 mg, 72.3%) as a white solid
LC-MS:m/z 774.3(M+1). 1 H NMR(400MHz,CDCl 3 )δ7.30(m,1H),7.17(t,J＝8.1Hz,1H),7.10(d,J＝8.3Hz,1H),6.87(d,J＝8.1Hz,1H),6.78(d,J＝8.0Hz,1H),6.64(d,J＝8.4Hz,1H),6.58–6.46(m,4H),6.43(m,2H),6.30(s,1H),6.00(s,1H),4.28(t,J＝6.1Hz,2H),4.21(t,J＝6.1Hz,2H),3.85(d,J＝9.3Hz,2H),3.79(s,3H),3.77(s,3H),3.63(s,3H),3.42(m,2H),3.30-3.20(m,2H),3.14(s,3H),3.0-2.80(m,8H),2.62-2.54(m,3H),2.44-2.33(m,2H),2.27(s,3H).
Example 8: synthesis of Compound 8
Prepared as in example 1 starting with 5-hydroxypyrimidine and BBM (200 mg,0.29 mmol) to give compound 8 (105.0 mg, 48.1%) as a white solid.
LC-MS:m/z 746.3(M+1).1H NMR(400MHz,CDCl 3 )δ8.84(s,1H),8.42(s,2H),7.12(dd,J＝30.2,8.3Hz,2H),6.91–6.81(m,2H),6.58(d,J＝23.7Hz,2H),6.41(s,2H),6.30(s,1H),6.00(s,1H),4.32(dt,J＝26.9,6.0Hz,4H),3.91(s,2H),3.78(d,J＝1.6Hz,3H),3.62(s,3H),3.47(m,2H),3.41–3.32(m,2H),3.14(s,3H),3.11–2.63(m,8H),2.62(s,3H),2.41–2.33(m,2H),2.30(s,3H).
Example 9: synthesis of Compound 9
Prepared as in example 1 starting with 3-hydroxyquinoline and BBM (400 mg,0.59 mmol) to give compound 9 (305.0 mg, 65.5%) as a white solid.
LC-MS:m/z 795.3(M+1).1H NMR(400MHz,CDCl 3 )δ8.67(d,J＝2.8Hz,1H),8.04(d,J＝8.3Hz,1H),7.66(d,J＝8.1Hz,1H),7.56(t,J＝7.3Hz,1H),7.49(t,J＝7.4Hz,1H),7.42(d,J＝2.9Hz,1H),7.24(d,J＝8.3Hz,1H),7.07(d,J＝8.4Hz,1H),6.90(d,J＝8.2Hz,1H),6.79(s,1H),6.56(d,J＝18.6Hz,2H),6.36(s,2H),6.29(s,1H),5.98(s,1H),4.36(dt,J＝17.5,6.1Hz,4H),3.85(s,2H),3.77(s,3H),3.62(s,3H),3.43(m,2H),3.24(m,2H),3.14(s,3H),3.10–2.63(m,8H),2.60(s,3H),2.42(m,2H),2.24(s,3H).
Example 10: synthesis of Compound 10
Prepared as in example 1 starting with p-fluorophenol and BBM (500 mg,0.73 mmol) to give compound 10 (400.0 mg, 72%) as a white solid.
LC-MS:m/z 762.3(M+1). 1 H NMR(400MHz,CDCl 3 )7.32(dd,J＝8.2,2.1Hz,1H),7.20(d,J＝7.9Hz,1H),7.12(s,1H),7.03–6.91(m,2H),6.86(dq,J＝6.6,4.3,3.2Hz,3H),6.63–6.54(m,2H),6.39(s,2H),6.32(s,1H),6.02(s,1H),4.27(t,J＝6.1Hz,2H),4.18(t,J＝6.0Hz,2H),4.03(m,2H),3.78(s,3H),3.62(s,3H),3.44(m,2H),3.20(m,2H),3.15(s,3H),3.09–2.73(m,8H),2.70(s,3H),2.37(s,2H),2.32-2.24(m,3H).
Example 11: synthesis of Compound 11
Prepared as in example 1 starting with hydroxypyrazine and BBM (200 mg,0.29 mmol) to give compound 11 (95 mg, 45%) as a white solid.
LC-MS:m/z 743.2(M+1). 1 H NMR(400MHz,CDCl 3 )δ8.22(d,J＝1.4Hz,1H),8.14–8.03(m,2H),7.22(d,J＝7.7Hz,1H),7.11(m,1H),6.86(d,J＝7.6Hz,1H),6.61(s,1H),6.56(s,1H),6.40(s,2H),6.31(s,1H),6.01(s,1H),4.58(t,J＝6.2Hz,2H),4.27(t,J＝6.3Hz,2H),3.95(m,2H),3.78(s,3H),3.63(s,3H),3.34(s,2H),3.24(s,2H),3.15(s,3H),3.0-2.80(m,8H),2.66(s,3H),2.41–2.20(m,5H).
Example 12: synthesis of Compound 12
Compound 10 (150 mg,0.20 mmol) was dissolved in 37% concentrated hydrochloric acid (1.5 mL). After stirring the solution, paraformaldehyde (15 mg,0.48 mmol) was added at 0℃and then stirred for 2h at 25-30 ℃. After completion of the reaction, acetonitrile (10.0 mL) was added to the reaction mixture, which was concentrated under reduced pressure, and acetonitrile (5.0 mL) and N-methylpiperazine (34 mg,0.48 mmol) were added to the organic phase after the concentration under reduced pressure. Then cooling to 0-5 ℃, adding NaH (23 mg,0.95 mmol), heating to 25-30 ℃ and stirring for 2h. After the reaction was completed, the reaction mixture was poured into water, extracted with DCM, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and isolated by column chromatography as a white solid compound 12 (47 mg, 30%).
LC-MS:m/z 874.3(M+1). 1 H NMR(400MHz,CDCl 3 )δ7.30(m,1H),7.09(dd,J＝8.1,2.5Hz,1H),7.00–6.91(m,2H),6.90–6.82(m,3H),6.78(d,J＝8.2Hz,1H),6.66(dd,J＝8.3,2.5Hz,1H),6.56(s,1H),6.45(m,2H),5.99(s,1H),4.28(t,J＝6.2Hz,2H),4.18(t,J＝6.0Hz,2H),3.90(d,J＝9.5Hz,2H),3.73(s,3H),3.62(s,3H),3.50-3.20(m,6H),3.17(s,3H),3.05-2.62(m,8H),2.60(s,3H),2.43(m,8H)2.33(m,2H),2.27(s,3H),2.24(m,3H)。
Example 13: synthesis of Compound 13
Prepared as in example 12 starting with compound 10 (140 mg,0.18 mmol) and piperidine to give compound 13 as a white solid (45 mg, 30%).
LC-MS:m/z 859.3(M+1).1H NMR(400MHz,CDCl 3 )δ7.30(m,1H),7.09(dd,J＝8.2,2.5Hz,1H),7.00–6.90(m,2H),6.86(dd,J＝8.9,4.4Hz,3H),6.77(d,J＝7.9Hz,1H),6.66(dd,J＝8.3,2.6Hz,1H),6.56(s,1H),6.45(d,J＝8.0Hz,2H),6.01(s,1H),4.28(t,J＝6.1Hz,2H),4.18(t,J＝6.0Hz,2H),3.89(m,2H),3.72(s,3H),3.62(s,3H),3.52–3.23(m,6H),3.17(s,3H),3.07–2.62(m,8H),2.60(s,3H)2.36–2.26(m,6H),2.24(s,3H),1.54-1.36(m,6H)。
Example 14: synthesis of Compound 14
Prepared as in example 12 starting with compound 10 (150 mg,0.20 mmol) and tetrahydropyrrole to give compound 14 (65 mg, 40%) as a white solid.
LC-MS:m/z 845.3(M+1). 1 H NMR(400MHz,CDCl 3 )δ7.30(m,1H),7.10(dd,J＝8.2,2.6Hz,1H),6.95(m,2H),6.86(m,3H),6.77(d,J＝8.0Hz,2H),6.66(dd,J＝8.3,2.6Hz,1H),6.55(s,1H),6.44(m,1H),6.02(s,1H),4.28(t,J＝6.1Hz,2H),4.18(t,J＝6.1Hz,2H),3.88(d,J＝9.6Hz,2H),3.72(s,3H),3.61(s,3H),3.54(d,J＝6.6Hz,2H),3.47-3.28(m,4H),3.17(s,3H),3.07–2.63(m,8H),2.61(s,3H),2.52-2.42(m,4H),2.32-2.4(m,2H),2.25(s,3H),1.80-1.72(m,4H).
Example 15: synthesis of Compound 15
Prepared as in example 12 starting with compound 10 (150 mg,0.20 mmol) and diethylamine to give compound 15 (55 mg, 34%) as a white solid.
LC-MS:m/z 846.4(M+1).1H NMR(400MHz,CDCl 3 )δ7.30(s,1H),7.11(dd,J＝8.1,2.5Hz,1H),6.95(t,J＝8.7Hz,2H),6.91–6.81(m,3H),6.78(s,1H),6.65(dd,J＝8.4,2.5Hz,1H),6.54(s,1H),6.51–6.40(m,2H),6.04(s,1H),4.28(t,J＝6.1Hz,2H),4.18(t,J＝6.1Hz,2H),3.90(s,2H),3.72(s,3H),3.60(s,3H),3.44–3.18(m,6H),3.17(s,3H),3.12–2.66(m,8H),2.61(s,3H),2.47(m,4H),2.32(p,J＝6.0Hz,2H),2.25(s,3H),1.02(s,6H).
Example 16: synthesis of Compound 16
Prepared as in example 12 starting with compound 10 (140 mg,0.18 mmol) and morpholine to give compound 16 (45 mg, 29%) as a white solid.
LC-MS:m/z 860.4(M+1).1H NMR(400MHz,CDCl 3 )δ7.30(s,1H),7.09(d,J＝8.9Hz,1H),6.95(t,J＝8.7Hz,2H),6.91–6.82(m,3H),6.79(s,1H),6.65(d,J＝8.6Hz,1H),6.56(s,1H),6.45(s,2H),5.99(s,1H),4.28(t,J＝6.2Hz,2H),4.18(t,J＝6.1Hz,2H),3.90(s,2H),3.73(s,3H),3.63(d,J＝11.7Hz,7H),3.54–3.22(m,6H),3.17(s,3H),3.09–2.63(m,8H),2.61(s,3H),2.39(s,4H),2.31(q,J＝6.0Hz,2H),2.26(s,3H).
Example 17: synthesis of Compound 17
Prepared as in example 12 starting with compound 9 (150 mg,0.19 mmol) and tetrahydropyrrole to give compound 17 (65.0 mg, 40%) as a white solid.
LC-MS:m/z 877.3(M+1).1H NMR(400MHz,CDCl 3 )δ8.67(d,J＝2.8Hz,1H),8.04(d,J＝8.3Hz,1H),7.66(d,J＝8.1Hz,1H),7.56(t,J＝7.3Hz,1H),7.49(t,J＝7.4Hz,1H),7.42(d,J＝2.9Hz,1H),7.24(d,J＝8.3Hz,1H),7.07(d,J＝8.4Hz,1H),6.90(d,J＝8.2Hz,1H),6.79(s,1H),6.56(d,J＝18.6Hz,2H),6.36(s,2H),5.98(s,1H),4.36(dt,J＝17.5,6.1Hz,4H),3.88(s,2H),3.72(s,3H),3.61(s,3H),3.55-3.19(m,6H),3.14(s,3H),3.10–2.63(m,8H),2.60(m,7H),2.42(m,2H),2.23(s,3H),1.80-1.72(m,4H).
Example 18: synthesis of Compound 18
Prepared as in example 12 starting with compound 9 (150 mg,0.19 mmol) and methylpiperazine to give compound 18 (55.0 mg, 32.3%) as a white solid.
LC-MS:m/z 906.3(M+1).1H NMR(400MHz,CDCl 3 )δ8.67(d,J＝2.8Hz,1H),8.04(d,J＝8.3Hz,1H),7.66(d,J＝8.1Hz,1H),7.56(t,J＝7.3Hz,1H),7.49(t,J＝7.4Hz,1H),7.42(d,J＝2.9Hz,1H),7.24(d,J＝8.3Hz,1H),7.07(d,J＝8.4Hz,1H),6.90(d,J＝8.2Hz,1H),6.80(s,1H),6.56(d,J＝18.6Hz,2H),6.39(s,2H),5.97(s,1H),4.42–4.30(m,4H),3.90(d,J＝9.5Hz,2H),3.73(s,3H),3.62(s,3H),3.50-3.20(m,6H),3.17(s,3H),3.05–2.63(m,8H),2.60(s,3H),2.51–2.34(m,10H),2.28(s,3H),2.24(m,3H).
Example 19: synthesis of Compound 19
Prepared as in example 12 starting with compound 3 (100 mg,0.12 mmol) and tetrahydropyrrole to give compound 19 (50 mg, 45.8%) as a white solid.
LC-MS:m/z 896.3(M+H). 1 H NMR(400MHz,CDCl 3 )δ8.37(d,J＝2.8Hz,1H),7.55(d,J＝8.7Hz,1H),7.33–7.23(m,2H),7.05(dd,J＝8.2,2.6Hz,1H),6.87(d,J＝8.1Hz,1H),6.78(d,J＝7.4Hz,1H),6.64–6.52(m,2H),6.48(s,1H),6.41(d,J＝8.2Hz,1H),6.00(s,1H),4.36(tt,J＝6.1,2.9Hz,2H),4.28(t,J＝5.9Hz,2H),3.87(d,J＝9.3Hz,2H),3.72(s,3H),3.61(s,3H),3.54(s,2H),3.49–3.18(m,4H),3.17(s,3H),3.07–2.62(m,8H),2.60(s,3H),2.47(m,4H),2.36(p,J＝6.0Hz,2H),2.23(s,3H),1.72(m,4H).
Example 20: synthesis of Compound 20
Prepared as in example 12 starting with compound 3 (100 mg,0.12 mmol) and methylpiperazine to give compound 20 (40 mg, 35.5%) as a white solid.
LC-MS:m/z 924.3(M+H). 1 H NMR(400MHz,CDCl 3 )δ8.38(d,J＝2.8Hz,1H),7.56(d,J＝8.8Hz,1H),7.34–7.23(m,2H),7.04(d,J＝8.6Hz,1H),6.87(d,J＝8.1Hz,1H),6.79(s,1H),6.63–6.53(m,2H),6.43(s,2H),5.98(s,1H),4.35(t,J＝5.9Hz,2H),4.29(t,J＝5.9Hz,2H),3.88(s,2H),3.72(s,3H),3.62(s,3H),3.55-3.24(m,6H),3.17(s,3H),3.13–2.67(m,8H),2.60(s,3H),2.56-2.39(m,8H),2.36(q,J＝6.0Hz,2H),2.30(s,3H),2.24(s,3H).
Example 21: synthesis of Compound 21
Prepared as in example 12 starting with compound 2 (100 mg,0.13 mmol) and tetrahydropyrrole to give compound 21 (30 mg, 27.9%) as a white solid.
LC-MS:m/z 827.3(M+H). 1 H NMR(400MHz,CDCl 3 )δ8.44–8.37(m,2H),7.26(d,1H),7.09(d,1H),6.89–6.79(m,3H),6.77(d,J＝8.2Hz,1H),6.64(dd,J＝8.3,2.5Hz,1H),6.55(s,1H),6.51–6.41(m,2H),6.01(s,1H),4.28(q,J＝6.3Hz,4H),3.88(d,J＝9.5Hz,2H),3.72(s,3H),3.61(s,3H),3.54(d,J＝6.2Hz,2H),3.43–3.20(m,4H),3.17(s,3H),3.05–2.62(m,8H),2.60(s,3H),2.47(m,4H),2.35(p,J＝6.1Hz,2H),2.24(s,3H),1.72(m,4H).
Example 22: synthesis of Compound 22
Prepared as in example 12 starting with compound 2 (100 mg,0.13 mmol) and methylpiperazine to give compound 22 (35 mg, 31.4%) as a white solid.
LC-MS:m/z 857.3(M+H). 1 H NMR(400MHz,CDCl 3 )δ8.40(d,J＝5.5Hz,2H),7.31(d,1H),7.09(d,1H),6.89–6.79(m,4H),6.65–6.53(m,2H),6.43(s,2H),6.01(d,J＝17.9Hz,1H),4.28(q,J＝6.4Hz,4H),3.93(t,J＝15.7Hz,2H),3.71(s,3H),3.61(s,3H),3.50–3.27(m,6H),3.16(s,3H),3.13–2.67(m,8H),2.62(s,3H),2.53(m,8H),2.39(s,3H),2.34(q,J＝6.0Hz,2H),2.26(m,3H).
Example 23: synthesis of Compound 23
Prepared as in example 12 starting with compound 4 (110 mg,0.14 mmol) and tetrahydropyrrole to give compound 23 (44 mg, 36.7%) as a white solid.
LC-MS:m/z 858.3(M+H),429.3(1/2M+H)1H NMR(400MHz,CDCl 3 )δ7.81(d,J＝3.0Hz,1H),7.34–7.19(m,2H),7.13(d,J＝8.2Hz,1H),6.88(s,2H),6.64(dd,J＝16.6,8.7Hz,2H),6.55(s,1H),6.46(s,1H),6.40(s,1H),6.05(s,1H),4.27(t,J＝6.1Hz,2H),4.20(t,J＝6.1Hz,2H),4.02(s,2H),3.89(s,3H),3.75(s,3H),3.60(s,3H),3.57-3.17(m,6H),3.15(s,3H),3.13-2.70(m,8H),2.66(s,3H),2.47(m,4H),2.30(d,J＝6.7Hz,5H),1.80-1.72(m,4H).
Example 24: synthesis of Compound 24
Prepared as in example 12 starting with compound 4 (110 mg,0.14 mmol) and methylpiperazine to give compound 24 (60 mg, 48.4%) as a white solid.
LC-MS:m/z 887.3(M+H). 1 H NMR(400MHz,CDCl 3 )δ7.82(d,J＝3.0Hz,1H),7.31(s,1H),7.23(dd,J＝9.0,3.1Hz,1H),7.11(s,1H),6.89(s,2H),6.70–6.54(m,3H),6.42(s,2H),5.99(s,1H),4.28(t,J＝6.1Hz,2H),4.20(t,J＝6.0Hz,2H),4.06(d,J＝8.0Hz,1H),3.95(s,1H),3.89(s,3H),3.71(s,3H),3.61(s,3H),3.52-3.21(m,6H),3.17(s,3H),3.14–2.70(m,8H),2.65(s,3H),2.63-2.48(m,8H),2.45(s,3H),2.31(m,5H).
Example 25: synthesis of Compound 25
Prepared as in example 1 starting with p-fluorophenol, 4-bromobutyloxy-t-butyldimethylsilane and BBM (100 mg,0.15 mmol) to give compound 25 (80 mg, 72%) as a white solid.
LC-MS:m/z 776.3(M+1). 1 H NMR(400MHz,CDCl 3 )δ7.32(dd,J＝8.2,2.1Hz,1H),7.20(d,J＝7.9Hz,1H),7.12(s,1H),6.97–6.90(m,2H),6.83(dq,J＝6.6,4.3,3.2Hz,3H),6.64–6.56(m,2H),6.39(s,2H),6.30(s,1H),6.00(s,1H),4.15(t,J＝6.1Hz,2H),4.05(t,J＝6.0Hz,2H),3.86(m,2H),3.78(s,3H),3.63(s,3H),3.46(m,2H),3.24(m,2H),3.15(s,3H),3.09–2.68(m,8H),2.61(s,3H),2.34-2.18(m,3H),2.02(m,4H).
Example 26: synthesis of Compound 26
Berberine hydrochloride (BBM, 0.5g,0.73 mmol) was suspended in 5mL of methylene chloride, cooled to 0-5℃and 180mg (1.78 mmol) of triethylamine and 150mg (0.79 mmol) of p-toluenesulfonyl chloride were added to the reaction mixture. After the addition, the temperature was raised to 25℃and the reaction was stirred for 1 hour. After the completion of the reaction, the reaction mixture was quenched with water, extracted with DCM, the organic phases were combined, dried over saturated brine, filtered and concentrated under reduced pressure to give the crude product, which was isolated and purified by column chromatography to give compound 26 (430 mg, 76.8%) as a white solid.
LC-MS:m/z 764.2(M+H),382.2(1/2M+H).1H NMR(400MHz,CDCl 3 )δ7.80(d,J＝8.1Hz,2H),7.25(t,J＝8.1Hz,3H),7.15(d,J＝8.1Hz,1H),6.84–6.73(m,2H),6.54(s,1H),6.36(s,2H),6.31–6.19(m,2H),5.93(s,1H),3.77(s,3H),3.62(s,3H),3.41-3.24(m,4H),3.13(s,3H),3.06–2.60(m,10H),2.59(s,3H),2.42(s,3H),2.23(m,3H).
Example 27: synthesis of Compound 27
Prepared as in example 1, starting with p-bromobenzenesulfonyl chloride and berbamine hydrochloride (BBM, 0.5g,0.73 mmol) to afford compound 27 (305 mg, 50.3%) as a white solid.
LC-MS:m/z 827.1(M+H),1H NMR(400MHz,CDCl 3 )δ7.78(d,J＝8.5Hz,2H),7.61(d,J＝8.3Hz,2H),7.25(m,1H),7.18(d,J＝8.2Hz,1H),6.84(d,J＝8.2Hz,1H),6.75(s,1H),6.56(s,1H),6.47-6.16(m,4H),5.93(s,1H),3.78(s,3H),3.62(s,3H),3.50-3.20(m,4H),3.13(s,3H),3.06–2.88(m,10H),2.61(s,3H),2.25(s,3H).
Example 28: synthesis of Compound 28
Prepared as in example 1, starting with 5-chlorothiophene sulfonyl chloride and berbamine hydrochloride (BBM, 0.5g,0.73 mmol) to afford compound 28 (400 mg, 69%) as a white solid.
LC-MS:m/z 789.1(M+H),1H NMR(400MHz,CDCl 3 )δ7.45(d,J＝4.1Hz,1H),7.30(m,1H),7.18(d,J＝8.2Hz,1H),6.93(d,J＝4.1Hz,1H),6.86(t,J＝8.8Hz,2H),6.56(s,1H),6.48-6.29(m,4H),5.95(s,0H),3.78(s,3H),3.63(s,3H),3.40-3.20(m,4H),3.14(s,3H),3.03-2.76(m,10H),2.61(s,3H),2.25(s,3H).
Example 29: synthesis of Compound 29
Prepared as in example 1, starting with thiophenesulfonyl chloride and berbamine hydrochloride (BBM, 0.5g,0.73 mmol) to afford compound 29 as a white solid (380 mg, 69%).
LC-MS:m/z 755.2(M+H),1H NMR(400MHz,CDCl 3 )δ7.68(t,J＝4.5Hz,2H),7.27(m,1H),7.16(d,J＝8.2Hz,1H),7.09(t,J＝4.4Hz,1H),6.85(d,J＝8.2Hz,2H),6.55-6.22(m,5H),5.94(s,1H),3.78(s,3H),3.63(s,3H),3.40-3.20(m,4H),3.14(s,3H),3.03-2.76(m,10H),2.61(s,3H),2.26(s,3H).
Example 30: synthesis of Compound 30
Prepared as in example 1, starting with p-trifluoromethylbenzenesulfonyl chloride and berbamine hydrochloride (BBM, 0.5g,0.73 mmol) to afford compound 30 (400 mg, 67%) as a white solid.
LC-MS:m/z 817.2(M+H),1H NMR(400MHz,CDCl 3 )δ8.06(d,J＝8.1Hz,1H),7.74(d,J＝8.1Hz,1H),7.22(t,J＝8.0Hz,1H),6.85(d,J＝8.2Hz,1H),6.67(s,1H),6.56(s,1H),6.47-6.16(m,4H),5.91(s,1H),3.78(s,3H),3.62(s,3H),3.50-3.20(m,4H),3.13(s,3H),3.06–2.88(m,10H),2.61(s,3H),2.25(s,3H).
Example 31: synthesis of Compound 31
Prepared as in example 1 using 3-pyridinesulfonyl chloride and berberine hydrochloride (BBM, 0.5g,0.73 mmol) as starting materials to give compound 31 (370 mg, 68%) as a white solid.
LC-MS:m/z 750.2(M+H),1H NMR(400MHz,CDCl 3 )δ9.07(d,J＝5.6Hz,1H),8.82(d,J＝5.0Hz,1H),8.25(d,J＝8.3Hz,1H),7.45–7.37(m,1H),6.86(d,J＝8.2Hz,1H),6.75(d,J＝8.1Hz,1H),6.54(s,1H),6.46-6.13(m,5H)5.92(s,1H),3.78(s,3H),3.62(s,3H),3.50-3.20(m,4H),3.13(s,3H),3.06–2.88(m,10H),2.61(s,3H),2.25(s,3H).
Example 32: synthesis of Compound 32
Prepared as in example 1 using p-bromobenzenesulfonyl chloride and berbamine hydrochloride (BBM, 0.5g,0.73 mmol) as starting materials to give compound 32 (385 mg, 69%) as a white solid.
LC-MS:m/z 768.2(M+H),1H NMR(400MHz,CDCl 3 )δ7.98–7.87(m,2H),7.26(dd,J＝8.2,2.0Hz,1H),7.20–7.07(m,3H),6.82(t,J＝10.5Hz,2H),6.55(s,1H),6.29(s,1H),6.42-6.13(m,3H)5.93(s,1H),3.78(s,3H),3.62(s,3H),3.50-3.20(m,3H,3.14(s,3H),3.08–2.88(m,10H),2.41(s,3H),2.24(s,3H).
Example 33: synthesis of Compound 33
Compound 32 (200.0 mg,0.26 mmol) was dissolved in 37% concentrated hydrochloric acid (2.0 mL). After the solvent was removed by stirring, paraformaldehyde (18.4 mg,0.613 mmol) was added at 0℃and then stirred at room temperature for 2 hours. After completion of the reaction, acetonitrile (10.0 mL) was added to the reaction mixture, the mixture was concentrated under reduced pressure, acetonitrile (5.0 mL) and N-methylpiperazine (45 mg,0.65 mmol) were added to the organic phase after the concentration under reduced pressure, the temperature was lowered to 0-5 ℃, naH (30 mg,1.3 mmol) was added, and the mixture was stirred for 2 hours at 25-30 ℃. After the reaction was completed, the reaction mixture was poured into water, extracted with DCM, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give the compound as a white solid (80.0 mg, 37%).
LC-MS:m/z 879.2(M+H),1H NMR(400MHz,CDCl 3 )δ7.95(dd,J＝8.6,4.9Hz,2H),7.25(dd,J＝8.3,2.0Hz,1H),7.14(t,J＝8.4Hz,3H),6.80(dd,J＝15.5,8.2Hz,2H),6.55(s,1H),6.39(s,2H),6.26(d,J＝8.1Hz,1H),5.93(s,1H),3.88–3.77(m,2H),3.70(s,3H),3.60(s,3H),3.50-3.20(m,8H),3.14(s,3H),3.04–2.62(m,6H),2.59(s,3H),2.41(brs,6H),2.59(s,3H),2.29(s,3H),2.20(s,3H)
Example 34: synthesis of Compound 34
Prepared as in example 33, starting with compound 32 (200.0 mg) to give compound 34 (90.0 mg, 41%) as a white solid.
LC-MS:m/z 851.3(M+H),1H NMR(400MHz,CDCl 3 )δ7.95(dd,J＝8.6,4.9Hz,2H),7.25(dd,J＝8.3,2.0Hz,1H),7.14(t,J＝8.4Hz,3H),6.80(dd,J＝15.5,8.2Hz,2H),6.55(s,1H),6.39(s,2H),6.26(d,J＝8.1Hz,1H),5.93(s,1H),3.90–3.74(m,2H),3.70(s,3H),3.56(s,3H),3.51-3.06(m,8H),3.04-2.74(m,7H),2.68(m,2H),2.58(s,3H),2.46(brs,4H),2.19(s,3H),2.11–1.97(m,4H).
Example 35: synthesis of Compound 35
Prepared as in example 33, starting with compound 27 (200.0 mg) to give compound 35 (85 mg, 38%) as a white solid.
LC-MS:m/z 910.1(M+H),1H NMR(400MHz,CDCl 3 )δ7.81–7.69(m,2H),7.60(d,J＝8.5Hz,2H),7.16(d,J＝8.1Hz,1H),6.80(dd,J＝19.0,8.0Hz,2H),6.54(s,1H),6.50-6.20(m,3H)5.98(s,1H),3.95–3.74(m,2H),3.70(s,3H),3.56(s,3H),3.51-3.07(m,8H),3.06-2.73(m,7H),2.68(m,2H),2.58(s,3H),2.45(brs,4H),2.33(s,1H),2.19(d,J＝4.9Hz,3H),2.12–1.98(m,4H).
Example 36: synthesis of Compound 36
Prepared as in example 33, starting with compound 27 (200.0 mg) to give compound 36 (80.0 mg, 36%) as a white solid.
LC-MS:m/z 939.2(M+H),1H NMR(400MHz,CDCl 3 )δ7.81–7.69(m,2H),7.60(d,J＝8.5Hz,2H),7.16(d,J＝8.1Hz,1H),6.80(dd,J＝19.0,8.0Hz,2H),6.54(s,1H),6.50-6.20(m,3H)5.98(s,1H),3.90–3.77(m,2H),3.71(s,3H),3.60(s,3H),3.50-3.20(m,8H),3.14(s,3H),3.04–2.62(m,6H),2.59(s,3H),2.40(brs,6H),2.59(s,3H),2.29(s,3H),2.20(s,3H)
Example 37: synthesis of Compound 37
Prepared as in example 33 starting with compound 30 (200.0 mg) to give compound 37 (90.0 mg, 40.9%) as a white solid.
LC-MS:m/z 901.2(M+1).1H NMR(400MHz,CDCl 3 )δ8.07(d,J＝8.2Hz,2H),7.74(d,J＝8.2Hz,2H),7.26–7.16(m,2H),6.85(d,J＝8.2Hz,1H),6.66(s,1H),6.55(s,1H),6.35(s,2H),6.15(d,J＝8.0Hz,1H),5.91(s,1H),3.88(d,J＝9.6Hz,2H),3.72(s,3H),3.61(s,3H),3.54(d,J＝6.6Hz,1H),3.42-3.28(m,6H),3.17(s,3H),3.09–2.73(m,7H),2.61(s,3H),2.52-2.42(m,4H),2.32-2.4(m,2H),2.25(s,3H),1.81-1.72(m,4H).
Example 38: synthesis of Compound 38
Prepared as in example 33 starting with compound 30 (200.0 mg) to give compound 38 (65.0 mg, 28.5%) as a white solid.
LC-MS:m/z 929.3(M+1).1H NMR(400MHz,CDCl 3 )δ8.07(d,J＝8.2Hz,2H),7.74(d,J＝8.2Hz,2H),7.26–7.16(m,2H),6.85(d,J＝8.2Hz,1H),6.66(s,1H),6.55(s,1H),6.35(s,2H),6.15(d,J＝8.0Hz,1H),5.91(s,1H),3.90–3.77(m,2H),3.73(s,3H),3.62(s,3H),3.50-3.20(m,8H),3.17(s,3H),3.04–2.62(m,6H),2.59(s,3H),2.40(brs,6H),2.59(s,3H),2.29(s,3H),2.20(s,3H)
Example 39: synthesis of Compound 39
Prepared as in example 33 starting with compound 26 (200.0 mg) to give compound 39 (80 mg, 45.13%) as a white solid.
LC-MS:m/z 847.3(M+H),423.8(1/2M+H).1H NMR(400MHz,CDCl 3 )δ7.81(d,J＝8.1Hz,2H),7.25(t,J＝7.8Hz,3H),7.14(d,J＝8.2Hz,1H),6.78(dd,J＝14.8,8.2Hz,2H),6.54(s,1H),6.38(s,2H),6.27(d,J＝8.3Hz,1H),5.96(s,1H),3.88(m,2H),3.71(s,3H),3.59(s,3H),3.54(s,2H),3.40(s,1H),3.30(s,1H),3.15(s,3H),2.96(t,J＝12.6Hz,3H),2.85(s,5H),2.68(d,J＝13.8Hz,2H),2.60(s,3H),2.47(s,4H),2.42(s,3H),2.20(s,3H),1.73(s,4H).
Example 40: synthesis of Compound 40
Prepared as in example 33 using compound 26 (200.0 mg) as a starting material to give compound 40 (75 mg, 40.9%) as a white solid.
LC-MS:m/z 877.3(M+H),438.3(1/2M+H).1H NMR(400MHz,CDCl 3 )δ7.84–7.77(m,2H),7.26(d,J＝7.8Hz,3H),7.13(d,J＝8.2Hz,1H),6.83(s,1H),6.75(s,1H),6.56(s,1H),6.39(s,2H),6.30(s,1H),5.92(s,1H),3.85(s,2H),3.71(s,3H),3.61(s,3H),3.49(d,J＝12.2Hz,2H),3.40(s,3H),3.24(s,2H),3.16(s,3H),3.05–2.93(m,2H),2.89(d,J＝16.7Hz,4H),2.70(s,2H),2.61(s,3H),2.49(s,7H),2.42(s,3H),2.36(s,3H),2.22(s,3H).
Example 41: synthesis of Compound 41
Prepared as in example 33 using compound 26 (200.0 mg) as a starting material to give compound 41 (96 mg, 47%) as a white solid.
LC-MS:m/z 861.2(M+H),430.8(1/2M+H).1H NMR(400MHz,CDCl 3 )δ7.81(d,J＝8.1Hz,2H),7.25(t,J＝8.9Hz,3H),7.14(d,J＝8.2Hz,1H),6.81(d,J＝8.2Hz,1H),6.74(d,J＝7.8Hz,1H),6.55(s,1H),6.38(s,2H),6.28(d,J＝8.5Hz,1H),5.94(s,1H),3.82(q,J＝9.7,9.2Hz,2H),3.71(s,3H),3.61(s,3H),3.40(d,J＝11.5Hz,2H),3.34–3.18(m,4H),3.15(s,3H),3.03–2.79(m,6H),2.74–2.63(m,2H),2.59(s,3H),2.42(s,3H),2.39–2.23(m,4H),2.21(d,J＝10.0Hz,3H),1.45(d,J＝32.9Hz,6H).
Example 42: synthesis of Compound 42
Prepared as in example 33 starting with compound 26 (200.0 mg) to give compound 42 (74 mg, 40.9%) as a white solid.
LC-MS:m/z 863.3(M+H),431.8(1/2M+H).1H NMR(400MHz,CDCl 3 )δ7.84–7.77(m,2H),7.25(t,J＝8.0Hz,3H),7.14(d,J＝8.0Hz,1H),6.81(d,J＝8.3Hz,1H),6.75(d,J＝7.9Hz,1H),6.55(s,1H),6.38(s,2H),6.28(d,J＝8.6Hz,1H),5.94(s,1H),3.83(d,J＝9.8Hz,2H),3.72(s,3H),3.64(s,4H),3.60(s,3H),3.46(d,J＝12.2Hz,2H),3.36(d,J＝12.8Hz,2H),3.24(s,2H),3.15(s,3H),3.06–2.64(m,8H),2.60(s,3H),2.42(s,3H),2.38(s,4H),2.30–2.13(m,3H).
Example 43: synthesis of Compound 43
Prepared as in example 33 using compound 26 (200.0 mg) as a starting material to give compound 43 (75 mg, 42.1%) as a white solid.
LC-MS:m/z 849.3(M+H),424.8(1/2M+H).1H NMR(400MHz,CDCl 3 )δ7.84–7.77(m,2H),7.25(t,J＝7.6Hz,3H),7.14(d,J＝8.1Hz,1H),6.78(dd,J＝14.9,8.2Hz,2H),6.53(s,1H),6.38(s,2H),6.26(dd,J＝8.3,2.5Hz,1H),5.97(s,1H),3.87(t,J＝8.1Hz,1H),3.79(d,J＝9.8Hz,1H),3.70(s,3H),3.58(s,3H),3.53(d,J＝12.3Hz,2H),3.40(d,J＝12.0Hz,2H),3.31–3.18(m,2H),3.15(s,3H),3.03–2.79(m,6H),2.65(dd,J＝13.9,9.7Hz,2H),2.59(s,3H),2.43(d,J＝10.9Hz,7H),2.19(s,3H),0.99(t,J＝7.0Hz,6H).
Example 44: synthesis of Compound 44
Prepared as in example 33 using compound 29 (200.0 mg) as a starting material to give compound 44 (150 mg, 54.7%) as a white solid.
LC-MS:m/z 839.2(M+H),419.7(1/2M+H).1H NMR(400MHz,CDCl 3 )δ7.68(dt,J＝3.9,1.4Hz,2H),7.26(dd,J＝8.3,2.0Hz,1H),7.18–7.05(m,2H),6.90–6.78(m,2H),6.59(s,0H),6.54(s,1H),6.44–6.31(m,3H),5.97(s,1H),3.91–3.83(m,1H),3.80(d,J＝9.9Hz,1H),3.71(s,3H),3.59(s,3H),3.53(d,J＝4.0Hz,2H),3.46–3.34(m,1H),3.23(s,3H),3.15(s,3H),3.10–2.74(m,6H),2.67(dd,J＝14.5,9.2Hz,2H),2.59(s,3H),2.48(d,J＝9.0Hz,4H),2.20(s,3H),1.79–1.66(m,4H).
Example 45: synthesis of Compound 45
Prepared as in example 33 starting with compound 29 (200.0 mg) to give compound 45 (100 mg, 35%) as a white solid.
LC-MS:m/z 868.3(M+H),436.3(1/2M+H). 1 H NMR(400MHz,CDCl 3 )δ7.69(dd,J＝4.1,2.2Hz,2H),7.26(d,J＝8.0Hz,1H),7.18–7.06(m,2H),6.84(t,J＝8.7Hz,2H),6.55(s,1H),6.44–6.33(m,3H),5.95(s,1H),3.84(s,2H),3.71(s,3H),3.61(s,3H),3.47(d,J＝12.2Hz,1H),3.38(s,2H),3.25(d,J＝9.1Hz,3H),3.15(s,3H),3.10–2.63(m,9H),2.59(s,3H),2.55–2.31(m,7H),2.27(s,3H),2.21(s,3H).
Example 46: synthesis of Compound 46
Prepared as in example 33 starting with compound 28 (200.0 mg) to give compound 46 (100 mg, 45.9%) as a white solid.
LC-MS:m/z 873.2(M+H),436.7(1/2M+H). 1 H NMR(400MHz,CDCl 3 )δ7.46(d,J＝4.0Hz,1H),7.36–7.25(m,1H),7.17(d,J＝8.1Hz,1H),6.95–6.80(m,3H),6.55(s,1H),6.47–6.36(m,3H),6.01(d,J＝18.5Hz,1H),3.85(dd,J＝34.7,9.1Hz,2H),3.71(s,3H),3.60(s,3H),3.53(d,J＝4.1Hz,2H),3.47–3.35(m,1H),3.34–3.19(m,3H),3.16(s,3H),3.05–2.77(m,6H),2.68(dd,J＝14.4,8.7Hz,2H),2.60(s,3H),2.47(s,4H),2.22(d,J＝10.4Hz,3H),1.73(d,J＝5.4Hz,4H).
Example 47: synthesis of Compound 47
Prepared as in example 33 starting with compound 28 (200.0 mg) to give compound 47 (80 mg, 35.5%) as a white solid.
LC-MS:m/z 901.2(M+H),451.8(1/2M+H). 1 H NMR(400MHz,CDCl 3 )δ7.46(d, J ＝4.1Hz,1H),7.29(d,J＝9.6Hz,1H),7.17(d,J＝8.1Hz,1H),6.96–6.81(m,3H),6.56(s,1H),6.46–6.36(m,3H),5.96(s,1H),3.89–3.79(m,2H),3.72(s,3H),3.62(s,3H),3.47(d,J＝12.2Hz,2H),3.38(s,2H),3.30–3.20(m,2H),3.15(s,3H),3.06–2.63(m,8H),2.60(s,3H),2.42(s,7H),2.27(s,3H),2.22(s,3H).
Example 48: synthesis of Compound 48
Prepared as in example 33 starting with compound 31 (200.0 mg) to give compound 48 (110 mg, 49.5%) as a white solid.
LC-MS:m/z 834.2(M+H),417.2(1/2M+H). 1 H NMR(400MHz,CDCl 3 )δ9.07(d,J＝2.3Hz,1H),8.82(dd,J＝4.9,1.5Hz,1H),8.24(dt,J＝8.1,2.0Hz,1H),7.41(dd,J＝8.1,4.9Hz,1H),7.22(t,J＝8.4Hz,2H),6.88–6.79(m,1H),6.77(d,J＝7.5Hz,1H),6.53(s,1H),6.37(d,J＝7.2Hz,2H),6.18(d,J＝7.9Hz,1H),5.95(s,1H),3.87(q,J＝8.5,7.8Hz,1H),3.76(d,J＝9.8Hz,1H),3.71(d,J＝3.7Hz,3H),3.59(s,3H),3.53(d,J＝2.9Hz,2H),3.35(ddd,J＝29.9,12.2,6.2Hz,2H),3.27–3.17(m,2H),3.15(s,2H),3.11–2.62(m,9H),2.59(d,J＝5.0Hz,3H),2.46(s,4H),2.20(s,3H)，1.73(d,J＝5.4Hz,4H).
Example 49: synthesis of Compound 49
Prepared as in example 33 starting with compound 31 (200.0 mg) to give compound 49 (90 mg, 39.1%) as a white solid.
LC-MS:m/z 863.3(M+H),431.7(1/2M+H). 1 H NMR(400MHz,CDCl 3 )δ9.07(d,J＝2.3Hz,1H),8.82(dd,J＝4.8,1.6Hz,1H),8.25(dt,J＝8.1,2.0Hz,1H),7.41(dd,J＝8.1,4.9Hz,1H),7.27–7.17(m,2H),6.85(d,J＝8.4Hz,1H),6.75(d,J＝8.3Hz,1H),6.54(s,1H),6.38(s,2H),6.19(d,J＝8.3Hz,1H),5.93(s,1H),3.85(s,1H),3.78(d,J＝9.5Hz,1H),3.70(s,3H),3.60(s,3H),3.46(d,J＝12.2Hz,2H),3.37(s,2H),3.37–3.20(m,2H),3.14(s,3H),3.11–2.61(m,9H),2.59(s,3H),2.54–2.32(m,7H),2.27(s,3H),2.20(s,3H).
Example 50: synthesis of Compound 50
Compound 40 (150 mg,0.17 mmol) was dissolved in EtOH (2 mL) and H 2 To a mixed solvent of O (1 mL), KOH (15 mg,0.27 mmol) was added, and the mixture was heated to 60-70℃and stirred for 3 hours. After completion of the reaction, H was added to the reaction mixture 2 O, extract with DCM, combine the organic phases, dry with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure to give the crude product, which is separated by column chromatography to give compound 50 (70 mg, 56.8%) as a white solid.
LC-MS:m/z 722.3(M+H),361.3(1/2M+H). 1 H NMR(400MHz,CDCl 3 )δ7.33(d,J＝7.3Hz,1H),7.12(dd,J＝8.2,2.6Hz,1H),6.88–6.77(m,2H),6.67(dd,J＝8.3,2.5Hz,1H),6.54(d,J＝10.9Hz,2H),6.38(s,1H),5.98(s,1H),3.96–3.85(m,2H),3.73(s,3H),3.60(s,3H),3.50(d,J＝12.2Hz,2H),3.38(s,2H),3.28(d,J＝6.7Hz,2H),3.24(s,2H),3.18(s,3H),3.10–2.63(m,7H),2.61(s,3H),2.43(s,7H),2.30(s,3H),2.26(s,3H).
Example 51: synthesis of Compound 51
Compound 39 (230 mg,0.27 mmol) was dissolved in EtOH (3 mL) and H 2 To a mixed solvent of O (1.5 mL), KOH (23 mg,0.41 mmol) was added, and the mixture was heated to 60-70℃and stirred for 3 hours. After completion of the reaction, H was added to the reaction mixture 2 O, extracting with DCM, mixing the organic phases, washing with saturated common salt water, anhydrous sodium sulfateDrying, filtration, and concentration under reduced pressure gave a crude product which was separated by column chromatography to give compound 51 (110 mg, 58.9%) as a white solid.
LC-MS:m/z 693.3(M+H),346.8(1/2M+H). 1 H NMR(400MHz,CDCl 3 )δ7.32(dd,J＝8.1,2.1Hz,1H),7.14(dd,J＝8.1,2.5Hz,1H),6.82(d,J＝8.0Hz,1H),6.75(dd,J＝8.1,1.8Hz,1H),6.66(dd,J＝8.3,2.5Hz,1H),6.53(s,1H),6.47(d,J＝9.3Hz,2H),6.03(s,1H),3.92(d,J＝9.4Hz,2H),3.71(s,3H),3.58(s,3H),3.54(d,J＝4.2Hz,2H),3.45(td,J＝16.7,14.4,10.9Hz,1H),3.34(s,1H),3.33–3.21(m,1H),3.16(s,3H),2.98(dd,J＝13.4,9.5Hz,3H),2.85(tq,J＝11.8,5.7,4.8Hz,4H),2.73–2.63(m,2H),2.60(s,3H),2.47(s,4H),2.23(s,3H),1.73(d,J＝5.4Hz,4H).
Example 52: the invention provides an anti-human T cell lymphoma and multiple myeloma cell activity determination method of berberine derivative
(1) Experimental materials
Tumor cell lines: human T cell lymphoma cell line H9 and multiple myeloma cell line RPMI8226 were purchased from ATCC pool in the united states.
Reagent:
berberine (BBM) standard was purchased from Sichuan shi 370225, pukang Biochemical Co., ltd,
the berbamine derivatives of the invention are shown in the table above.
The main instrument is as follows: cell incubator and enzyme-labeled instrument
(2) Experimental method
H9 and RPMI-8226 cells with good growth were inoculated into 96-well cell culture plate wells, respectively, and the number of cells was 7000 cells/well. The culture medium is 1640 cell culture medium containing 10% of fetal bovine serum. Adding berberine compounds with different concentrations, mixing, and adding into carbon dioxide (5% CO) 2 ) The cells were cultured at 37℃in a cell incubator for 72 hours. Viable cell concentration was then determined using the MTT method. In this experiment, the cell viability of the control group (no compound addition treatment) was set to 100%, and the cell viability (%) after the compound action and the half growth inhibition concentration of tumor cells at 72 hours (72 hours IC were calculated 50 Values).
(3) Experimental results
The experimental results are shown in Table 1. Table 1 shows that the berbamine derivative of the invention can obviously inhibit the growth of T cell lymphoma strain H9 and myeloma cell strain RPMI8226, and compared with berbamine itself, the activity of the berbamine derivative for resisting tumor cells is obviously enhanced. Experimental results show that when the carbon at position 5 of the structural formula of the berbamine is substituted or the phenolic hydroxyl group is substituted as defined herein, the resulting berbamine derivative exhibits better activity against T-cell lymphoma and multiple myeloma cells than berbamine; when the carbon at position 5 of the berbamine structure and the phenolic hydroxyl group are simultaneously substituted as defined herein, the resulting berbamine derivatives will exhibit significantly better activity against T-cell lymphoma and multiple myeloma cells than monosubstituted (e.g., carbon at position 5 substituted or phenolic hydroxyl group substituted) derivatives.
TABLE 1 Activity assay (72 hours IC 50. Mu.M)
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Claims (5)

1. A berbamine derivative represented by the general formula (I):
wherein n=1-15;
w is selected from methylene;
x is selected from nitrogen;
R 1 、R 2 each independently selected from H, C 1 -C 10 An alkyl group; or R is 1 、R 2 With X to form a substituted or unsubstituted C 3 -C 7 A heterocyclic group; the C is 3 -C 7 The heterocyclic group is selected from pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydroimidazolyl and tetrahydropyrazolyl; wherein the substitution is selected fromSubstituted from the following groups: halogen, amino, hydroxy, C 1 -C 6 One or more of alkyl groups;
y is selected from O;
z is selected from R 6 Wherein R is 6 Selected from the group consisting of substituted or unsubstituted phenyl, pyridyl and quinolinyl, wherein said substitution means substitution with a group selected from the group consisting of: halogen, amino, hydroxy, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 One or more of alkoxy groups;
R 3 、R 4 each independently selected from H.
2. The berbamine derivative or pharmaceutically acceptable salt thereof according to claim 1, selected from:
3. a process for preparing a berbamine derivative of general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, comprising:
step one: reacting the compound (II) with hydroxyl-protected bromoor iodoalcohol (III) under alkaline conditions to obtain a compound (IV); wherein PG is a hydroxyl protecting group;
step two: removing protecting group PG from the generated compound (IV), and then reacting with an activating reagent to obtain a compound (V); LG is a leaving group;
step three: reacting berbamine (BBM) with a compound (V) under an alkaline condition to obtain a berbamine derivative (I-A);
step four: reacting the berberine derivative (I-A) with formaldehyde and hydrochloric acid in the presence of zinc dichloride to generate a 5-chloromethyl berberine derivative (I-A');
step five: reacting a berbamine derivative (I-A') with R under alkaline conditions 1 R 2 NH reaction to produce 5-substituted berberine derivative shown in general formula (I);
wherein n, R 1 、R 2 、R 3 、R 4 Y, Z are as defined for formula (I).
4. A pharmaceutical composition comprising the berbamine derivative of any one of claims 1-2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
5. Use of a berbamine derivative according to any one of claims 1-2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 4, for the manufacture of an anti-tumour medicament, said tumour being selected from multiple myeloma, lymphoma.
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Citations (4)

* Cited by examiner, † Cited by third party
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CN101273989A (en) * 2008-04-09 2008-10-01 浙江大学 Berbamine derivative and application of salt thereof
WO2012031563A1 (en) * 2010-09-10 2012-03-15 杭州本生药业有限公司 Heterocyclic amino berbamine derivatives, preparation method and use thereof
WO2013026383A1 (en) * 2011-08-19 2013-02-28 杭州本生药业有限公司 Tetrandrine derivatives with substituted 5-carbon, preparation method and use thereof
CN107033157A (en) * 2016-02-03 2017-08-11 贵州省中国科学院天然产物化学重点实验室 Bisbenzylisoquinolinderivative derivative and its purposes in preparing for treating or preventing the medicine of tumour

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US8722698B2 (en) * 2009-05-19 2014-05-13 City Of Hope Berbamine derivatives

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101273989A (en) * 2008-04-09 2008-10-01 浙江大学 Berbamine derivative and application of salt thereof
WO2012031563A1 (en) * 2010-09-10 2012-03-15 杭州本生药业有限公司 Heterocyclic amino berbamine derivatives, preparation method and use thereof
WO2013026383A1 (en) * 2011-08-19 2013-02-28 杭州本生药业有限公司 Tetrandrine derivatives with substituted 5-carbon, preparation method and use thereof
CN107033157A (en) * 2016-02-03 2017-08-11 贵州省中国科学院天然产物化学重点实验室 Bisbenzylisoquinolinderivative derivative and its purposes in preparing for treating or preventing the medicine of tumour

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