WO2014008838A1 - 芳基取代甲基连接的双吲哚乙酸衍生物及其制备方法和应用 - Google Patents
芳基取代甲基连接的双吲哚乙酸衍生物及其制备方法和应用 Download PDFInfo
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- WO2014008838A1 WO2014008838A1 PCT/CN2013/078908 CN2013078908W WO2014008838A1 WO 2014008838 A1 WO2014008838 A1 WO 2014008838A1 CN 2013078908 W CN2013078908 W CN 2013078908W WO 2014008838 A1 WO2014008838 A1 WO 2014008838A1
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- hydroxyphenyl
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention relates to a biguanide acetic acid derivative, particularly an aryl-substituted methyl-linked biguanide acetic acid derivative having antitumor activity.
- the present invention also relates to a process for the preparation of the aryl-substituted methyl-linked bis-indoleacetic acid derivative, and its use as an antitumor drug. Background technique
- Tumor treatments include surgery, radiation therapy, and medication (chemotherapy). At present, chemotherapy is still the main means of clinical treatment of tumors.
- Finding anti-tumor drugs is one of the hot spots in new drug research. Recently, the development of anti-tumor drugs has shifted from conventional cytotoxic chemotherapeutic agents to more mechanism-based targeting to prevent tumor growth.
- the DNA of tumor cells is one of the most important targets for antitumor drugs. Antitumor drugs acting on tumor cell DNA can destroy the structure and function of tumor cell DNA by directly acting on DNA, and can also inhibit DNA synthesis by interacting with DNA.
- the drug is embedded in the ditch area of DNA and is an important anti-tumor mechanism.
- a biguanide acetic acid derivative linked only by a methyl group such as the following structure 3b (1-(3-carboxymethylindol-1-yl-methyl)-indole-3) -acetic acid) and 4b (2-(3-carboxymethylindole-2-yl-methyl)-indole-3-acetic acid), or an aliphatic hydrocarbyl-substituted methyl-linked bis-indoleacetic acid derivative (eg The following structure 6b ([ 2 -(3-carboxymethylindole- 2 -yl)propan- 2 -yl]-indole-3-acetic acid)) can be inserted into the tumor DNA without significant neurotoxicity. However, its anti-tumor activity is not ideal.
- R is hydrogen or dC 6 alkyl
- Ar is an aryl group which is unsubstituted or substituted with one or more substituents which may be the same or different, and the substituent is selected from the group consisting of halogen, hydroxy, nitro, C r C 6 alkane a group consisting of an oxy group, a methylenedioxy group, and an ethylenedioxy group.
- the inventors obtained a novel aryl-substituted methyl group by structurally modifying a conventional aliphatic hydrocarbyl-substituted methyl-linked bis-indoleacetic acid derivative (such as the aforementioned 6b compound) by substituting the substituted aryl group (Ar) for the aliphatic hydrocarbon group.
- the linked biguanide acetic acid derivative not only greatly enhances the antitumor activity, but also significantly reduces neurotoxicity and toxic side effects.
- the invention also provides a process for the preparation of a compound of formula I above, as well as a pharmaceutical composition comprising a compound of formula I above.
- the invention also provides the use of a compound of formula I above for the preparation of an anti-tumor drug. detailed description
- R is hydrogen or dC 6 alkyl
- Ar is an aryl group which is unsubstituted or substituted by one or more substituents which may be the same or different, and the substituent is selected from the group consisting of halogen, hydroxy, nitro, dC 6 alkoxy a group consisting of methylenedioxy and ethylenedioxy.
- C r C 6 alkyl means a saturated straight or branched acyclic hydrocarbon having from 1 to 6 carbon atoms.
- Representative saturated linear alkyl groups include: methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl; and saturated branched alkyl groups include: isopropyl, sec-butyl, isobutyl, tert-Butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl and 4-methylpentyl.
- dC 6 in the compound of formula I The alkyl group may preferably be a dC 4 alkyl group, and more preferably a methyl group or an ethyl group.
- halogen means fluorine, chlorine or bromine, preferably chlorine.
- dC 6 alkoxy is a dC 6 alkyl group as defined above attached via an oxygen linkage to another moiety, preferably dC 4 alkoxy, more preferably methoxy, or ethoxy. , the most preferred is methoxy.
- Ar in the compound of formula I represents an unsubstituted or substituted aryl group, preferably an aryl group substituted with one to three identical or different substituents. That is, Ar may be a one to five substituted aryl group, preferably a monosubstituted, disubstituted or trisubstituted aryl group, and the positions of the respective substituents may be ortho to the carbon attached to the biguanide group. Replace with, meta or para.
- aryl refers to a functional group or substituent derived from a C 5 -C 8 aromatic ring.
- the aryl group may preferably be a phenyl group, ie, Ar may be a monosubstituted, disubstituted or trisubstituted phenyl group.
- the substituent of the monosubstituted phenyl group may preferably be a group consisting of chlorine, a hydroxyl group, a nitro group and a methoxy group, and the position of the substituent may be ortho or meta or to the carbon attached to the biguanide group.
- Para-substituted for example, ortho, meta- or p-hydroxyphenyl; o-, m- or p-chlorophenyl; o-, m- or p-nitrophenyl; o-, m- or p-methoxyphenyl; o-, m- or p-hydroxyphenyl.
- the substituent of the disubstituted phenyl group may preferably be a group consisting of chlorine, a hydroxyl group, a nitro group, a methoxy group, and a methylenedioxy group.
- the disubstituted phenyl groups may have the same or different two substituents, and the positions of the respective substituents may be ortho, meta or to the carbon attached to the bis-indoleacetic acid group. Replacement by position.
- the two substituents may be adjacent, interphase or opposite to each other.
- the disubstituted phenyl group may be 2,3-dihydroxyphenyl, 2,4-dihydroxyphenyl, 2,5-dihydroxyphenyl, 2,6-dihydroxyphenyl, 3,4-Dihydroxyphenyl, or 3,5-dihydroxyphenyl.
- the disubstituted phenyl group may be 2-methoxy 3-hydroxyphenyl, 2-methoxy-4 hydroxyphenyl, 2-methoxy-5 hydroxyphenyl.
- the disubstituted phenyl group may be 2,3-methylenedioxyphenyl or 3,4-methylenedioxyphenyl.
- the substituent of the trisubstituted phenyl group may preferably be a group consisting of chlorine, a hydroxyl group, a nitro group, a methoxy group, and a methylenedioxy group.
- the substituent of the trisubstituted phenyl group may be three identical or different substituents, or may be two identical and one different substituent; when a methylenedioxy group is substituted, the other substituent may be Chlorine, hydroxyl, nitro, or methoxy.
- the position of each substituent may be substituted with an ortho, meta or para position attached to the carbon of the biguanide group.
- the two substituents may be adjacent, interphase or opposite to each other.
- the substitution position may be selected from any three of the five carbons which may be substituted on the benzene ring.
- the three substituents may be consecutive adjacent (eg, 3,5-dimethoxy-4-hydroxyphenyl, 2,4-dimethoxy-3- Hydroxyphenyl, 3,4- Dimethoxy-5-hydroxyphenyl, or 2,3-dimethoxy-4-hydroxyphenyl), two adjacent and one non-adjacent (eg 2,3-dimethoxy-5-) Hydroxyphenyl, 3,4-dimethoxy-6-hydroxyphenyl, 2,5-dimethoxy-3-hydroxyphenyl, or 3,6-dimethoxy-4-hydroxyphenyl) Or the three substituents are not adjacent (such as 2,4-dimethoxy-6-hydroxyphenyl, or 2,6-dimethoxy-4-hydroxyphenyl).
- the monosubstituted, disubstituted or trisubstituted phenyl group of the compound of formula I of the present invention may preferably be selected from p-hydroxyphenyl, p-chlorophenyl, m-nitrophenyl, 3-methoxy-4- Hydroxyphenyl, 3,5-dimethoxy-4-hydroxyphenyl, 3,4-dihydroxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4 a group consisting of methylenedioxyphenyl, 2-hydroxy-4-carboxyphenyl, and 2-hydroxyphenyl.
- R in the compound of the formula I may be a methyl group or an ethyl group, and a compound represented by the following formula la lb is obtained:
- Ar is as defined above, and may preferably be selected from p-hydroxyphenyl, p-chlorophenyl, m-nitrophenyl, 3-methoxy-4-hydroxyphenyl, 3,5-dimethoxy-4-hydroxyphenyl. , 3,4-dihydroxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4-methylenedioxyphenyl, 2-hydroxy-4-carboxyphenyl And a group consisting of 2-hydroxyphenyl groups.
- R in the compound of formula I can be hydrogen, resulting in a compound of formula Ic:
- Ar is as defined above, and may preferably be selected from p-hydroxyphenyl, p-chlorophenyl, m-nitrophenyl, 3-methoxy-4-hydroxyphenyl, 3,5-dimethoxy-4-hydroxyphenyl. , 3,4-dihydroxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4-Asia A group consisting of methyl dioxyphenyl, 2-hydroxy-4-carboxyphenyl, and 2-hydroxyphenyl.
- Another aspect of the invention provides a pharmaceutical composition comprising the aforementioned compound of the invention, and a pharmaceutically acceptable carrier.
- the compound of the pharmaceutical composition of the present invention is preferably a compound represented by the above formulas Ia, lb and Ic.
- the pharmaceutical composition of the present invention can be used as an antitumor drug. That is, the present invention also provides the use of the compound for the preparation of an antitumor drug, the pharmaceutical composition comprising the compound of the present invention, which can be used for inhibiting tumor growth.
- a pharmaceutically acceptable carrier means a conventional pharmaceutical carrier in the pharmaceutical field, for example: a diluent, an excipient (such as water, etc.), a filler (such as starch, sucrose, etc.), a binder (such as a cellulose derivative, algae) Acid salts, gelatin and polyvinylpyrrolidone, humectants (such as glycerin), disintegrants (such as agar, calcium carbonate and sodium bicarbonate), absorption enhancers (such as quaternary compounds, etc.), surfactants (such as hexadecanol), adsorption carriers (such as kaolin and soap clay), lubricants (such as talc, calcium and magnesium stearate, and polyethylene glycol, etc.).
- a diluent such as water, etc.
- an excipient such as water, etc.
- a filler such as starch, sucrose, etc.
- a binder such as a cellulose derivative, algae
- the pharmaceutical composition of the present invention can be administered to a patient in need of such treatment by oral, nasal inhalation, rectal or parenteral administration.
- oral administration it can be formulated into conventional solid preparations such as tablets, powders, granules, capsules, etc., into liquid preparations such as water or oil suspensions or other liquid preparations such as syrups; for parenteral administration
- liquid preparations such as water or oil suspensions or other liquid preparations such as syrups
- parenteral administration In this case, it can be made into a solution for injection, water or an oily suspension, and the like.
- Preferred forms are tablets, coated tablets, capsules, suppositories, nasal sprays and injections.
- the various dosage forms of the pharmaceutical compositions of the present invention can be prepared according to conventional methods of production in the pharmaceutical arts. For example, the active ingredient is mixed with one or more carriers which are then brought into the preparations which are required.
- a further aspect of the invention provides a process for the preparation of a compound of formula I according to the invention, comprising:
- the compound of formula I is obtained by Ar H.
- R of the compound of formula I is hydrogen
- the solvent system is an inert solvent
- R is dC 6 alkyl
- the solvent system is the corresponding dC 6 alkanol.
- the catalyst may be concentrated sulfuric acid or concentrated hydrochloric acid, preferably concentrated sulfuric acid.
- C r C 6 alkanol means a saturated straight or branched chain alkanol containing from 1 to 6 carbon atoms.
- Representative saturated linear alkanols include: methanol, ethanol, n-propanol, n-butanol, n-pentanol, n-hexanol; and saturated branched alkanols include: isopropanol, sec-butanol, isobutanol, tert-butyl Alcohol, isoamyl alcohol, 2-methylbutanol, 3-methylbutanol, 2-methylpentanol, 3-methylpentanol and 4-methylpentanol.
- the solvent system is a 6- alkanol, preferably a 4- alkanol, more preferably methanol or ethanol.
- dC 6 alkanol can be used as a modifier to modify the acetate group on indole acetic acid and can be used simultaneously It is the solvent for the condensation reaction.
- R is a C r C 6 alkyl group.
- the R in the compound of the formula I obtained is methyl or ethyl (such as the compound of the above formula la or lb), and the synthetic route diagram thereof may preferably be as follows:
- Ar is as defined above, and may preferably be selected from p-hydroxyphenyl, p-chlorophenyl, m-nitrophenyl, 3-methoxy-4-hydroxyphenyl, 3,5-dimethoxy-4-hydroxyphenyl. , 3,4-dihydroxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4-methylenedioxyphenyl, 2-hydroxy-4-carboxyphenyl And a group consisting of 2-hydroxyphenyl groups.
- the solvent system is an inert solvent, which may preferably be selected from the group consisting of diethyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, dimethyl sulfoxide (DMSO), dimethylformamide. (DMF) The group formed.
- the inert solvent is more preferably anhydrous tetrahydrofuran.
- an inert solvent generally refers to a solvent which does not react with indole acetic acid or a substituted aldehyde having the formula P.
- Ar is as defined above, and may preferably be selected from p-hydroxyphenyl, p-chlorophenyl, m-nitrophenyl, 3-methoxy-4-hydroxyphenyl, 3,5-dimethoxy-4-hydroxyphenyl. , 3,4-dihydroxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4-methylenedioxyphenyl, 2-hydroxy-4-carboxyphenyl And a group consisting of 2-hydroxyphenyl groups.
- the preparation method of the present invention comprises condensing indole acetic acid and an aryl-substituted aldehyde in the presence of a catalyst, and
- the C r C 6 alkanol is optionally added to modify the acetate group on the indole acetic acid.
- the aryl-substituted methyl-linked bis-indole acetic acid derivative of the present invention can be obtained by a preparation method of the present invention in a one-pot reaction, which simplifies the preparation process and is advantageous for large-scale industrial mass production.
- the dC 6 alkanol can serve as both a solvent and a modifier (modifying an acetate group on indole acetic acid), which is advantageous in industrial production to further reduce costs.
- Example 5 Preparation of bis ⁇ [(1H-indol-3-yl)-acetic acid methyl ester]-2-yl ⁇ -(3-methoxy-4-hydroxyphenyl)-methane (M5) as in Example 1 Method, from lg (5.3 mmol) indole-3-acetic acid, 30 ml of methanol and 410 mg (2.7 mmol) of 3-methoxy-4-hydroxybenzaldehyde to give 1.0 g (72%) of solid.
- Example 1 1.25 g (85%) was obtained from lg (5.3 mmol) of indole-3-acetic acid, 30 ml of methanol and 490 mg (2.7 mmol) of 3,5-dimethoxy-4-hydroxybenzaldehyde.
- the target compound is a colorless particulate solid.
- IR (KBr) 3743, 3386, 2950, 2842, 2361, 1726, 1615, 1516, 1458, 1326, 1274, 1214, 1 167, 1 1 12, 1023, 917, 839, 806, 743, 662, 593, 548 , 474.
- Example 1 According to the method of Example 1, 1.1 g (82%) of the title compound was obtained from lg (5.3 mmol) indole-3-acetic acid, 30 ml of methanol and 370 mg (2.7 mmol) of 3,4-dihydroxybenzaldehyde. Red solid.
- Example 10 Preparation of bis ⁇ [(1H-indol-3-yl)-methyl acetate]-2-yl ⁇ -(3,4 -Methylenedioxyphenyl)-carboxamidine (M10) According to the method of Example 1, from lg (5.3 mmol) of indole-3-acetic acid, 30 ml of methanol and 405 mg (2.7 mmol) of 3,4- Methyldioxybenzaldehyde gave 1.0 g (;73%) of the desired compound as a pale yellow solid.
- Example 11 Preparation of bis ⁇ [(1H-indol-3-yl)-acetic acid methyl ester]-2-yl ⁇ -(2-hydroxy-4-carboxyphenyl)-carbamidine (Mil) According to Example 1 Method, 1.0 g (; 70%) of the title compound was obtained from lg (5.3 mmol) of indole-3-acetic acid, 30 ml of methanol and 450 mg (2.7 mmol) of 2-hydroxy-4-carboxybenzaldehyde as a lyophilic solid.
- Example 16 Preparation of bis ⁇ [(1H-indol-3-yl)-ethyl acetate]-2-yl ⁇ -(3-methoxy-4-hydroxyphenyl)-methane (E5) according to Example 12. Method, from lg (5.3 mmol) indole-3-acetic acid, 30 ml of ethanol and 410 mg (2.7 mmol) of 3-methoxy-4-hydroxybenzaldehyde to give 1.1 g (76%) of solid.
- Example 20 Preparation of bis ⁇ [(1H-indol-3-yl)-ethyl acetate]-2-yl ⁇ -(3,4-dimethoxyphenyl)-formamidine (E9)
- Example 12 Method, from 1 g (5.3 mmol) of indole-3-acetic acid, 30 ml of ethanol and 450 mg (2.7 mmol) of 3,4-dimethoxybenzaldehyde to give 1.2 g (80%) of the title compound as colorless powder.
- IR (KBr): 3742, 3361, 3057, 2978, 2933, 2905, 2836, 2362, 1887, 1719, 1592, 1550, 1514, 1458, 1414, 1369, 1313, 1267, 1146, 1100, 1030, 938, 848 , 743, 678, 600, 551, 477, 437.
- Example 21 Preparation of bis ⁇ [(1H-indol-3-yl)-ethyl acetate]-2-yl ⁇ -(3,4-methylenedioxyphenyl)-formamidine (E10) according to Example Method of 12, from 1 g (5.3 mmol) of indole-3-acetic acid, 30 ml of ethanol and 405 mg (2.7 mmol) of 3,4-methylenedioxybenzaldehyde to give 800 mg (55%) of the title compound. It is a colorless powder.
- Example 22 Preparation of bis ⁇ [(1H-indol-3-yl)-ethyl acetate]-2-yl ⁇ -(2-hydroxy-4-carboxyphenyl)-formamidine (E11) according to Example 12.
- Method 1.0 g (67%) of the title compound m. m. IR (KBr): 3859, 3742, 3673, 3650, 3370, 3059, 2982, 2362, 1713, 1616, 1558, 1489, 1458, 1370, 1338, 1304, 1272, 1 182, 1099, 1029, 929, 840, 803, 743, 673, 592, 548, 437.
- Example 28 Preparation of bis ⁇ [(IH-indol-3-yl)-acetic acid]-2-yl ⁇ -(3,5-dimethoxy-4-hydroxyphenyl)-methane (C6).
- Method 23 from 348 mg (2 mmol) indole-3-acetic acid and 181 mg (1 mmol) 3,5-two Methoxy-4-hydroxybenzaldehyde gave 300 mg (57%) of the title compound.
- the compounds of one of Ml-Mll, El-Ell or Cl-Cll of the present invention were each prepared in a cell culture medium containing 0.1% DMSO.
- a total of S 180 (mouse sarcoma cells), C6 (rat glioma cells), K562 (chronic granulocyte leukemia cells), HepG2 (hepatocellular carcinoma cells) and MCF-7 (human breast cancer cells) 5 were used. Tumor cells.
- HepG2, MCF-7, S180, C6 and K562 cells which grew well in the logarithmic growth phase, were seeded in 96-well plates at a density of 5 ⁇ 10 4 /mL, 100 ⁇ l per well. Incubate for 4 hours in a 37 ° C, 5% C0 2 incubator, and add the respective concentration gradients of 400 ⁇ , 40 ⁇ , 10 ⁇ , 5 ⁇ , 1 ⁇ , 100 ⁇ , 5 ⁇ 1 ⁇ to the sterilized solution.
- the compound of the present invention uses doxorubicin as a control.
- the compound of one of Ml-Mll, El-Ell or Cl-Cll of the present invention was separately dissolved in Tween 80 to dissolve in physiological saline.
- S 18Q sarcoma inoculated in ICR mice for 7-10 days under aseptic conditions, and the appropriate amount of physiological saline was added to prepare a tumor cell suspension, and the number of cells was 2 ⁇ 10 7 /mL, which was inoculated into the forearm of the healthy male ICR mice. Each mouse was injected with 0.2 ml.
- mice in the treatment group were intraperitoneally injected with 0.2 ml of an aqueous solution of Ml-Mll, El-Ell or Cl-Cll for 7 days, at a dose of 0.25 ⁇ 1/13 ⁇ 4.
- the mice in the blank group were intraperitoneally injected with 0.2 ml of normal saline daily.
- Doxorubicin dose was 2 ⁇ /kgM ⁇ positive control. The experiment was carried out until the 8th day, the weight of the mice was weighed, and the tumor weight of each group of mice was taken, and the tumor inhibition rate of each group of animals was finally counted.
- Tumor weight inhibition rate% (1 - administration group tumor weight / blank group tumor weight) x l00%.
- Compound activity is expressed by tumor weight or percent tumor inhibition rate , the data is listed in Table 2.
- doxorubicin did not show anti-tumor effects at doses below 2 mol/kg.
- doxorubicin did not show anti-tumor effects at doses below 2 mol/kg.
- the mice began to die on the fourth day of treatment, and no mice survived on the fifth day, indicating lethal toxicity.
- the mice showed neurotoxic symptoms such as convulsions and restlessness.
- Ml-Mll, E1-E11 and C1-C11 compounds all showed potent anti-tumor effects at a dose of 0.25 ⁇ /kg.
- the compound of Ml-Mll, E1-E11 or C1-C11 did not cause any mouse death, ie, no lethal toxicity, nor did it cause neurotoxic symptoms such as agitation and restlessness in the mice. Therefore, in the body against tumors, The compounds of the present invention are effective in inhibiting tumorigenesis at a dose of one-eighth of the doxorubicin dose, and the compounds of the present invention are also much lower than doxorubicin in terms of lethal toxicity and neurotoxicity.
- the inventors measured the in vivo antitumor activity of the compounds of 3b, 4b and 6b found in the previous studies according to the method of Experimental Example 2. .
- the measurement showed that the compounds of 3b, 4b and 6b had no antitumor effect at the dose of 0.25 ⁇ /kg used for the compound of one of M1-M11, E1-E11 or C1-C11 of the present invention.
- the 6b compound also showed only weak antitumor activity (see Table 3 for the results).
- n 12. a) Compared with the saline group and the doxorubicin group, p ⁇ 0.01.
- the compounds of the present invention not only greatly enhance antitumor activity, but also significantly reduce neurotoxicity and toxic side effects, compared to conventional bis-indoleacetic acid derivatives or analogs which are only linked by a methyl group or an aliphatic hydrocarbyl-substituted methyl group.
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Abstract
本发明提供了通式I代表的新颖的芳基取代甲基连接的双吲哚乙酸衍生物及其制备方法和应用。本发明的芳基取代甲基连接的双吲哚乙酸衍生物具有抑制肿瘤细胞功效且毒副作用弱,可作为临床用的抗肿瘤药物。
Description
芳基取代甲基连接的双吲哚乙酸衍生物及其制备方法和应用 技术领域
本发明涉及双吲哚乙酸衍生物,特别是具抗肿瘤活性的芳基取代甲基连接的双吲哚 乙酸衍生物。 本发明还涉及所述芳基取代甲基连接的双吲哚乙酸衍生物的制备方法, 及 其作为抗肿瘤药物的应用。 背景技术
恶性肿瘤是一种严重威胁人类健康的常见病,人类因恶性肿瘤而引起的死亡率在所 有疾病死亡率中居第二位, 仅次于心脑血管疾病。 肿瘤的治疗方法有手术治疗、 放射治 疗和药物治疗 (化学治疗)。 目前, 化学治疗仍然是临床治疗肿瘤的主要手段。 寻找抗肿 瘤药物是新药研究的热点之一。 最近, 抗肿瘤药物的开发已经从常规的细胞毒性化疗剂 转移至更基于机理的靶向阻止肿瘤生长。 肿瘤细胞的 DNA是抗肿瘤药物最重要的作用 靶点之一。 作用于肿瘤细胞 DNA的抗肿瘤药物既可以通过直接作用于 DNA来破坏肿 瘤细胞 DNA的结构和功能, 也可以通过与 DNA相互作用抑制 DNA的合成。 药物嵌入 DNA 的沟区, 是一种重要的抗肿瘤机制。 在发明人先前的研究中发现, 仅由甲基连接 的双吲哚乙酸衍生物 (如以下结构 3b (1-(3-羧基甲基吲哚 -1-基-甲基) -吲哚 -3-乙酸)和 4b (2-(3-羧基甲基吲哚 -2-基-甲基) -吲哚 -3-乙酸), 或是脂肪烃基取代甲基连接的双吲哚乙酸 衍生物 (如以下结构 6b ([2-(3-羧基甲基吲哚 -2-基)丙 -2-基] -吲哚 -3-乙酸))能够嵌插到肿瘤 的 DNA , 且没有明显的神经毒性, 然而其抗肿瘤活性未尽理想。
为了进一步提高甲基连接的或脂肪烃基取代甲基连接的双吲哚乙酸衍生物的抗肿 瘤活性, 且进一步降低神经毒性, 需要一种确实具有抑制肿瘤细胞功效且毒副作用弱的 新颖的双吲哚乙酸衍生物。 发明内容
为了达成提高双吲哚乙酸衍生物的抗肿瘤活性且进一步降低毒副作用的目的,本发
明提供了一种式 I化合物:
其中 R为氢或 d-C6烷基; Ar为未取代、或被一个或多个相同或不同的取代基取代的芳 基, 所述取代基选自卤素、 羟基、 硝基、 CrC6烷氧基、 亚甲二氧基、 亚乙二氧基所构 成的群组。 发明人经由以所述取代芳基 (Ar)代替脂肪烃基对习知的脂肪烃基取代甲基连 接的双吲哚乙酸衍生物 (如前述 6b 化合物)进行结构修饰而得到新颖的芳基取代甲基连 接的双吲哚乙酸衍生物, 其不仅大大提高了抗肿瘤活性, 且显著降低了神经毒性与毒副 作用。
本发明还提供了上述式 I化合物的制备方法, 以及包含上述式 I化合物的药物组合 物。 本发明还提供了上述式 I化合物在制备抗肿瘤药物中的应用。 具体实施方式
如上所述, 本发明提供了一种式 I化合物:
其中 R为氢或 d-C6烷基; Ar为未取代、或被一个或多个相同或不同的取代基取代的芳 基, 所述取代基选自卤素、 羟基、 硝基、 d-C6烷氧基、 亚甲二氧基、 亚乙二氧基所构 成的群组。
当用于本文, CrC6烷基意谓具有 1至 6个碳原子的饱和直链或支链无环烃。 代表 性饱和直链烷基包括: 甲基、 乙基、 正丙基、 正丁基、 正戊基、 正己基; 而饱和支链烷 基包括: 异丙基、 仲丁基、 异丁基、 叔丁基、 异戊基、 2-甲基丁基、 3-甲基丁基、 2-甲 基戊基、 3-甲基戊基及 4-甲基戊基。 在本发明的一个实施例中, 式 I化合物中的 d-C6
烷基可优选为 d-C4烷基, 更可优选为甲基或乙基。
当用于本文, 卤素意谓氟、 氯或溴, 优选为氯。
当用于本文, d-C6烷氧基为经由氧连接基与另一部分附接的如上定义的 d-C6烷 基, 可优选为 d-C4烷氧基, 更可优选为甲氧基、 或乙氧基, 最佳为甲氧基。
式 I化合物中的 Ar代表未取代或取代芳基, 优选为被一个至三个相同或不同的取 代基取代的芳基。 也就是说, Ar可为一至五取代的芳基, 优选为单取代、 双取代或三 取代的芳基, 而各个取代基的位置可与附接于双吲哚乙酸基团的碳成邻位、 间位或对位 取代。 当用于本文, 芳基是指从 C5-C8芳香环衍生出的官能团或取代基。 在本发明的一 个实施例中, 芳基可优选为苯基, 即 Ar可为单取代、 双取代或三取代苯基。
单取代苯基的取代基可优选自氯、 羟基、 硝基、 甲氧基所构成的群组, 取代基的位 置可与附接于双吲哚乙酸基团的碳成邻位、间位或对位取代,例如邻、间或对羟基苯基; 邻、 间或对氯苯基; 邻、 间或对硝基苯基; 邻、 间或对甲氧基苯基; 邻、 间或对羟基苯 基。
双取代苯基的取代基可优选自氯、羟基、硝基、 甲氧基、亚甲二氧基所构成的群组。 除亚甲二氧基取代以外, 双取代苯基可有相同或不同的两个取代基, 而各取代基的位置 可与附接于双吲哚乙酸基团的碳成邻位、 间位或对位取代。 两个取代基彼此之间可为相 邻、 相间或相对。 以两个羟基取代为例, 双取代苯基可为 2,3-二羟基苯基、 2,4-二羟基 苯基、 2,5-二羟基苯基、 2,6-二羟基苯基、 3,4-二羟基苯基、 或 3,5-二羟基苯基。 以一个 甲氧基和一个羟基取代为例, 双取代苯基可为 2-甲氧基 3-羟基苯基、 2-甲氧基 -4羟基苯 基、 2-甲氧基 -5羟基苯基、 2-甲氧基 -6羟基苯基、 2-羟基 -3-甲氧基苯基、 3-甲氧基 -4-羟 基苯基、 3-甲氧基 -5-羟基苯基、 3-甲氧基 -6-羟基苯基、 2-羟基 -4-甲氧基苯基、 或 3-羟基 -4-甲氧基苯基。 以亚甲二氧基取代为例, 双取代苯基可为 2,3-亚甲二氧基苯基、 或 3,4- 亚甲二氧基苯基。
三取代苯基的取代基可优选自氯、羟基、硝基、 甲氧基、亚甲二氧基所构成的群组。 三取代苯基的取代基可为三个相同或互不相同的取代基、或可为两个相同和一个不同的 取代基; 当有亚甲二氧基取代时, 则另一个取代基可为氯、 羟基、 硝基、 或甲氧基。 各 取代基的位置可与附接于双吲哚乙酸基团的碳成邻位、 间位或对位取代。 两个取代基彼 此之间可为相邻、 相间或相对。 如同双取代苯基所例示的, 当有三个取代基时, 其取代 位置可选自苯环上可供取代的五个碳中的任三个。 以两个甲氧基和一个羟基取代为例, 三个取代基可为连续相邻 (如 3,5-二甲氧基 -4-羟基苯基、 2,4-二甲氧基 -3-羟基苯基、 3,4-
二甲氧基 -5-羟基苯基、 或 2,3-二甲氧基 -4-羟基苯基)、 两个相邻而一个不相邻 (如 2,3-二 甲氧基 -5-羟基苯基、 3,4-二甲氧基 -6-羟基苯基、 2,5-二甲氧基 -3-羟基苯基、 或 3,6-二甲 氧基 -4-羟基苯基)、 或是三个取代基皆不相邻 (如 2,4-二甲氧基 -6-羟基苯基、 或 2,6-二甲 氧基 -4-羟基苯基)。 当有亚甲二氧基取代时, 其可任选为 2,3-、 或 3,4-位置的取代, 而另 一取代基可位在苯环上可供取代的三个碳中的任一个。
在一实施例中, 本发明式 I化合物中的单取代、 双取代或三取代苯基可优选自对羟 基苯基、对氯苯基、 间硝基苯基、 3-甲氧基 -4-羟基苯基、 3,5-二甲氧基 -4-羟基苯基、 3,4- 二羟基苯基、 4-甲氧基苯基、 3,4-二甲氧基苯基、 3,4-亚甲二氧基苯基、 2-羟基 -4-羧基苯 基、 和 2-羟基苯基所构成的群组。
本发明所述经取代苯基的取代基组合和取代位置包括本领域普通技术人员依据本 发明所能思及的各种排列组合, 以上例示说明不应视为对本发明的限制。
在本发明的又一实施例中, 式 I化合物中的 R可为甲基或乙基, 而得到分别如以下 通式 la lb所示的化合物:
Ar定义同上, 并可优选自对羟基苯基、 对氯苯基、 间硝基苯基、 3-甲氧基 -4-羟基苯基、 3,5-二甲氧基 -4-羟基苯基、 3,4-二羟基苯基、 4-甲氧基苯基、 3,4-二甲氧基苯基、 3,4-亚 甲二氧基苯基、 2-羟基 -4-羧基苯基、 和 2-羟基苯基所构成的群组。
在本发明化合物的再一实施例中, 式 I化合物中的 R可为氢, 而得到如以下通式 Ic 所示的化合物:
Ar定义同上, 并可优选自对羟基苯基、 对氯苯基、 间硝基苯基、 3-甲氧基 -4-羟基苯基、 3,5-二甲氧基 -4-羟基苯基、 3,4-二羟基苯基、 4-甲氧基苯基、 3,4-二甲氧基苯基、 3,4-亚
甲二氧基苯基、 2-羟基 -4-羧基苯基、 和 2-羟基苯基所构成的群组。
本发明的另一方面提供了一种药物组合物, 包含前述本发明化合物, 及药学上可接 受的载剂。 在一实施例中, 本发明药物组合物中的化合物, 优选为以上通式 Ia、 lb和 Ic 所示的化合物。 本发明药物组合物可作为抗肿瘤药物。 也就是说, 本发明还提供了所述 的化合物在制备抗肿瘤药物中的应用, 包含本发明化合物的所述药物组合物, 可用于抑 制肿瘤生长。 药学上可接受的载剂是指药学领域常规的药物载体, 例如: 稀释剂、 赋形 剂 (如水等)、 填充剂 (如淀粉、 蔗糖等)、 粘合剂 (如纤维素衍生物、 藻酸盐、 明胶和聚乙 烯毗咯垸酮等)、 湿润剂 (如甘油)、 崩解剂 (如琼脂、 碳酸钙和碳酸氢钠)、 吸收促进剂 (如 季按化合物等)、 表面活性剂 (如十六垸醇)、 吸附载体 (如高岭土和皂粘土)、 润滑剂 (如滑 石粉、 硬脂酸钙和镁、 和聚乙二醇等)。 本发明药物组合物可通过口服、 鼻吸入、 直肠 或肠胃外给药的方式施用于需要这种治疗的患者。 用于口服时, 可将其制成常规的固体 制剂如片剂、 粉剂、 粒剂、 胶囊等, 制成液体制剂如水或油悬浮剂或其它液体制剂如糖 浆剂等; 用于肠胃外给药时, 可将其制成注射用的溶液、 水或油性悬浮剂等。 优选的形 式是片剂、 包衣片剂、 胶囊、 栓剂、 鼻喷雾剂和注射剂。 本发明药物组合物的各种剂型 可以按照药学领域的常规生产方法制备。 例如使活性成分与一种或多种载体混合, 然后 将其制成所需的剂型。
本发明的又一方面是提供本发明式 I化合物的制备方法, 包括:
在催化剂存在下的溶剂系统中縮合吲哚乙酸和具有以下通式 P的经取代醛,
o
_ 、 ν
Ar H 而得到所述式 I化合物, 当式 I化合物的 R为氢时, 所述溶剂系统为惰性溶剂, 而当 R 为 d-C6烷基时, 所述溶剂系统为相应的 d-C6烷醇。 本发明制备方法中式 I化合物的 各取代基定义与前述相同。
本发明制备方法中所述催化剂可为浓硫酸或浓盐酸, 优选为浓硫酸。
当用于本文, CrC6烷醇意谓含有 1至 6个碳原子的饱和直链或支链烷醇。 代表性 饱和直链烷醇包括: 甲醇、 乙醇、 正丙醇、 正丁醇、 正戊醇、 正己醇; 而饱和支链烷醇 包括: 异丙醇、 仲丁醇、 异丁醇、 叔丁醇、 异戊醇、 2-甲基丁醇、 3-甲基丁醇、 2-甲基 戊醇、 3-甲基戊醇及 4-甲基戊醇。
在本发明制备方法的一实施例中, 溶剂系统为 6烷醇, 优选为 4烷醇, 更 优选为甲醇或乙醇。 d-C6烷醇可作为修饰剂以修饰吲哚乙酸上的乙酸基, 并可同时做
为縮合反应的溶剂。 因此, 当溶剂系统为 CrC6烷醇, 则 R为 CrC6烷基。 例如, 当溶 剂系统为甲醇或乙醇时, 所制得的式 I化合物中的 R为甲基或乙基 (如前述通式 la或 lb 的化合物), 其合成路线图可优选如下:
Ar定义同上, 并可优选自对羟基苯基、 对氯苯基、 间硝基苯基、 3-甲氧基 -4-羟基苯基、 3,5-二甲氧基 -4-羟基苯基、 3,4-二羟基苯基、 4-甲氧基苯基、 3,4-二甲氧基苯基、 3,4-亚 甲二氧基苯基、 2-羟基 -4-羧基苯基、 和 2-羟基苯基所构成的群组。
在本发明制备方法的另一实施例中, 溶剂系统为惰性溶剂, 所述惰性溶剂可优选自 乙醚、 四氢呋喃、 乙二醇二甲醚、 二甲基亚砜 (DMSO) 、 二甲基甲酰胺 (DMF) 构成 的群组。 所述惰性溶剂更可优选为无水四氢呋喃。 当用于本文, 惰性溶剂是泛指不会与 吲哚乙酸或具有通式 P的经取代醛产生反应的溶剂。 当溶剂系统为惰性溶剂时, 所制得 的式 I化合物其 R为氢 (如前述通式 Ic的化合物), 其合成路线图可优选如下:
Ar定义同上, 并可优选自对羟基苯基、 对氯苯基、 间硝基苯基、 3-甲氧基 -4-羟基苯基、 3,5-二甲氧基 -4-羟基苯基、 3,4-二羟基苯基、 4-甲氧基苯基、 3,4-二甲氧基苯基、 3,4-亚 甲二氧基苯基、 2-羟基 -4-羧基苯基、 和 2-羟基苯基所构成的群组。
本发明的制备方法包括在催化剂的存在下将吲哚乙酸和经芳基取代的醛縮合, 并可
选择性的加入 CrC6烷醇以修饰吲哚乙酸上的乙酸基。 利用本发明的制备方法可在一锅 反应下制得本发明的芳基取代甲基连接的双吲哚乙酸衍生物, 可简化制备工艺, 有利于 大规模工业量产。 d-C6烷醇可同时作为溶剂以及修饰剂 (修饰吲哚乙酸上的乙酸基), 在 工业生产上有利于进一步降低成本。
申请人藉由肿瘤细胞模型和移植性小鼠 S 180肉瘤模型, 评价了本发明芳基取代甲 基连接的双吲哚乙酸衍生物的体外和体内抗肿瘤活性, 及观察其致命性毒性和神经毒 性, 由此确认了本发明芳基取代甲基连接的双吲哚乙酸衍生物确实具有显著的抗肿瘤疗 效, 并且没有明显的细胞毒性或毒副作用。
为了进一步阐述本发明, 下面给出一系列实施例。 这些实施例完全是范例性的, 它 们仅用来对本发明进行更具体描述, 并不对本发明的范围构成任何限制。 本领域技术人 员应该理解的是,在不偏离本发明的精神和范围下可以对本发明技术方案的细节和形式 进行修改或替换, 但这些修改和替换应视为落入本发明的保护范围内。 本发明通式 la化合物 (M1-M11)的制备方法
实施例 1 制备双 {[(1H-吲哚 -3-基) -乙酸甲酯】 -2-基 }-(4-羟基苯基) -甲垸(Ml)
将 lg (5.3 mmol ) 吲哚 -3-乙酸溶于 30 ml甲醇,往里滴加 1 ml浓硫酸和 320 mg (2.7 mmol) 对羟基苯甲醛, 室温反应 48 h, 减压浓縮除去溶剂, 残留物经柱层析分离得到 1.2 g (91%)标题化合物, 为粉红色固体。 IR (KBr) 3388, 3056, 2951 , 1719, 1615, 1512, 1457, 1437, 1341 , 1307, 1221 , 1 170, 1 103, 1018, 833, 745, 553, 472。 i iNMR (300M DMSO-d6): δ/ppm =10.62 (s 2Η), 9.38 (s 1Η), 7.44 (d
2H), 7.34 (d J=8.1Hz 2H), 7.04 (m 6H), 6.72 (d J=8.7Hz 2H), 6.00 (s 1H), 3.68 (s 4H), 3.48 (s 6H)。 13C NMR (75M DMSO-d6): δ/ppm = 172.4, 156.5, 136.6, 136.0, 131.1 , 129.7, 128.3, 121.4, 1 19.2, 1 18.5, 1 15.5, 1 1 1.6, 105.3, 51.9, 29.8。 FAB-MS (m/e): 505 [M+Na]+, Mp 95。C。 实施例 2制备双 {[(1H-吲哚 -3-基) -乙酸甲酯】 -2-基 }-(4-氯苯基) -甲垸(M2)
将 1 g (5.3 mmol ) 吲哚 -3-乙酸溶于 30 ml甲醇,往里滴加 1 ml浓硫酸和 380 mg (2.7 mmol) 对氯苯甲醛, 室温反应 48 h, 减压浓縮除去溶剂, 残留物用乙酸乙酯溶解, 得到 的溶液先用饱和 NaHC03洗 3次, 再用和饱和 NaCl水溶液洗 3次, 乙酸乙酯层用无水 Na2S04干燥过夜, 过滤, 减压浓縮除去溶剂。 通过乙酸乙酯-石油醚体系重结晶, 得到 1 g(77%)标题化合物, 为无色针状晶体。 IR (KBr) 3854, 3385, 3058, 2951 , 2284, 1723, 1622, 1510, 1489, 1458, 1435, 1406, 1642, 1313, 1207, 1240, 1 167, 1 108, 1016, 852, 816,
745, 658, 489。 'HNMR (300M DMSO-d6): δ/ppm = 10.67 (s 2H), 7.43 (m 4H), 7.35 (d J=7.8Hz 2H),7.05 (t /=6.9Hz J=7.5Hz 2H), 6.98 (t /=6.9Hz J=7.5Hz 2H), 6.14 (s 1H), 3.76 (s 4H), 3.47 (s 6H)。 13C NMR (75M DMSO-d6): δ/ppm =172.3, 140.1, 136.1 , 135.5, 131.9,
130.7, 128.8, 128.2, 121.7, 1 19.3, 1 18.6, 1 1 1.7, 105.7, 51.9, 29.7。 FAB-MS (mle) 523 [M + Na]+,Mp 55。C。
实施例 3制备双 {[(1H-吲哚 -3-基) -乙酸甲酯】 -2-基 }-(4-硝基苯基) -甲垸(M3)
按照实施例 1 的方法, 从 lg (5.3 mmol ) 吲哚 -3-乙酸, 30 ml甲醇和 410 mg (2.7 mmol)对硝基苯甲醛得到 820 mg (66% )标题化合物,为淡黄色固体。 IR (KBr) 3386, 3058, 2952, 1725, 1599, 1520, 1491, 1459, 1437, 1348, 1271 , 1239, 1 167, 1 108, 1016, 852, 816, 745, 658, 489。 i iNMR (300M DMSO-d6): δ/ppm = 10.73 (s 2Η), 8.24 (d
2Η), 7.57 (d
2Η), 7.10 (t
2Η), 6.33 (s 1Η), 3.76 (s 4Η), 3.47 (s 6Η)。 13C NMR (75M DMSO-d6): δ/ppm = 172.2, 149.0, 146.9, 136.2, 134.8, 136.2, 134.8, 130.2, 128.2, 124.1 ,
121.8, 1 19.4, 1 18.7, 1 1 1.8, 106.1 , 51.9, 29.7。 FAB-MS (m/e) 534 [M + Na]+, Mp 81。C。 实施例 4制备双 {[(1H-吲哚 -3-基) -乙酸甲酯】 -2-基 }-(3-硝基苯基) -甲垸(M4)
按照实施例 1 的方法, 从 lg (5.3 mmol ) 吲哚 -3-乙酸, 30 ml甲醇和 410 mg (2.7 mmol) 间硝基苯甲醛得到 1.2 g (;87%)标题化合物, 为淡黄色固体。 IR (KBr) 3381 , 3058, 2951 , 1727, 1617, 1583, 1530, 1488, 1459, 1435, 1270, 1239, 1 167, 1 100, 1018, 928, 848, 806, 745, 673, 590, 541, 502, 435。 ^MR (300M DMSO-d6): δ/ppm = 10.76 (s 2Η), 8.19 (m 1Η), 8.05 (s 1Η), 7.67 (d
2Η), 7.1 1 (t
2Η), 6.37 (s 1Η), 3.76 (s 4Η), 3.46 (s 6Η)。 13C NMR (75Μ DMSO-d6): δ/ppm = 172.2, 148.4, 143.5, 136.3, 135.7, 134.9, 130.4, 128.3, 123.5, 122.4, 121.8, 1 19.5, 1 18.8, 1 1 1.9, 106.1, 51.9, 29.7。 FAB-MS (mle) 534 [M + Na]+o Mp 81。C。
实施例 5制备双 {[(1H-吲哚 -3-基) -乙酸甲酯】 -2-基 }-(3-甲氧基 -4-羟基苯基) -甲烷(M5) 按照实施例 1的方法, 从 lg (5.3 mmol ) 吲哚 -3-乙酸, 30 ml甲醇和 410 mg (2.7 mmol) 3-甲氧基 -4-羟基苯甲醛得到 1.0 g(72%) 标题化合物, 为粉紫色固体。 IR (KBr) 3386, 3056, 2950, 2844, 1724, 1607, 1514, 1459, 1435, 1342, 1273, 1237, 1 168, 1028, 933, 850, 797, 744, 597, 550, 475。 ^MR (300M DMSO-d6): δ/ppm = 10.60 (s 2Η), 8.93 (s 1Η),
7.43 (d J=7.8Hz 2H), 7.35 (d J=8.1Hz 2H), 7.06 (t J=6.9Hz J=7.2Hz 2H), 6.98 (t J=6.9Hz J=7.2Hz 2H), 6.84 (d J=1.5Hz 1H), 6.74 (d J=8.1Hz 1H), 6.59 (dd J=1.5Hz J=8.1Hz 1H), 5.99 (s 1H), 3.66 (s 3H), 3.64 (s 4H), 3.43 (s 6H)。 13C NMR (75M DMSO-d6): δ/ppm = 172.4, 148.0, 145.9, 136.5, 136.0, 131.6, 128.4, 121.4, 121.3, 1 19.2, 1 18.5, 1 15.7, 1 13.4, 1 1 1.7, 105.1, 60.2, 51.8, 29.7。 FAB-MS (m/e) 535 [M + Na Mp 58。C。
实施例 6 制备双 {[(1H-吲哚 -3-基) -乙酸甲酯】 -2-基 }-(3,5-二甲氧基 -4-羟基苯基) -甲烷 (M6)
按照实施例 1的方法, 从 lg (5.3 mmol ) 吲哚 -3-乙酸, 30 ml甲醇和 490 mg (2.7 mmol) 3,5-二甲氧基 -4-羟基苯甲醛得到 1.25 g (85%)目标化合物, 为无色颗粒状固体。 IR (KBr) 3743, 3386, 2950, 2842, 2361 , 1726, 1615, 1516, 1458, 1326, 1274, 1214, 1 167, 1 1 12, 1023, 917, 839, 806, 743, 662, 593, 548, 474。 1腿 MR (300M DMSO-d6): δ/ppm = 10.61 (s 2Η), 8.32 (s 1Η), 7.44 (d
2Η), 6.99 (t
2Η), 6.59 (s 2Η), 5.99 (s 1Η), 3.68 (s 6Η), 3.63 (s 4Η), 3.48 (s 6Η)。 13C NMR (75Μ DMSO-d6): δ/ppm = 172.4, 148.4, 136.4, 135.9, 135.1 , 130.7, 128.5, 121.4, 1 19.2, 1 18.5, 1 1 1.8, 107.0, 101.1 , 59.5, 51.8, 29 FAB-MS (m/e) 565 [M + Na]+。 Mp 85。C。 实施例 7制备双 {[(1H-吲哚 -3-基) -乙酸甲酯】 -2-基 }-(3,4-二羟基苯基) -甲垸(M7)
按照实施例 1的方法, 从 lg (5.3 mmol ) 吲哚 -3-乙酸, 30 ml甲醇和 370 mg (2.7 mmol) 3,4-二羟基苯甲醛得到 1.1 g (82%)目标化合物, 为紫红色固体。 IR (KBr) 3387, 3056, 2952, 1718, 161 1, 1521 , 1489, 1459, 1438, 1342, 1279, 1 171 , 1 1 10, 1019, 853, 745, 588, ^MR (300M DMS0-d6): δ/ppm = 10.63 (s 2Η), 8.89 (d J=3.9Hz 1H), 8.82 (d J=3.6Hz 1H), 7.46 (d J=7.5Hz 2H), 7.35 (d J=7.8Hz 2H), 7.06 (t J=6.9Hz J=7.2Hz 2H), 7.00 (t /= 7.2Hz J=7.2Hz 2H), 6.69 (d /=7.1Hz 1H), 6.54(S 1H), 6.39(d J=7.8Hz 1H), 5.97 (S 1H), 3.71 (s 4H), 3.51 (s 6H)。 13C NMR (75M DMS0-d6): δ/ppm =172.4, 145.6, 145.5, 136.5, 135.9, 131.7, 128.2121.4, 1 19.2, 1 18.5, 1 1 1.6, 105.2, 60.3, 51.9, 29.8。 FAB-MS (m/e) 521 [M + Na]+。 Mp 70。C。
实施例 8制备双 {[(1H-吲哚 -3-基) -乙酸甲酯】 -2-基 }-(4-甲氧基苯基) -甲垸(M8)
按照实施例 1的方法, 从 lg (5.3 mmol ) 吲哚 -3-乙酸, 30 ml甲醇和 410 mg (3.0 mmol) 4-甲氧基苯基甲醛得到 1.3 g (;94%)标题化合物, 为淡蓝色固体。 IR (KBr) 3742, 3388, 3056, 2951 , 2841 , 2362, 1724, 1618, 1592, 1510, 1459, 1437, 1341 , 1274, 1241 , 1214, 1169, 1 130, 1024, 849, 744, 592。 i iNMR (300M DMS0-d6): δ/ppm = 10.65 (s 2Η), 8.97 (s
1H), 7.45 (d J=7.5Hz 2H), 7.35 (d J=7.8Hz 2H), 7.07 (t J=7.2Hz J=7.2Hz 2H), 6.98 (t J=7.2Hz J=7.2Hz 2H), 6.87 (d J=7.4Hz 1H), 6.59 (d J=1.5Hz 1H), 6.50 (d J=7.4Hz 1H), 6.00 (slH), 3.74 (s 4H), 3.71 (s 4H), 3.50 (s 6H)。 13C NMR (75M DMSO-d6): δ/ppm = 172.4, 146.9, 146.8, 136.4, 136.0, 133.4, 128.3, 121.5, 1 19.4, 1 19.2, 1 18.6, 1 16.1, 1 12.7, 1 1 1.7, 105.3, 56.1, 51.9, 29.8。 FAB-MS (m/e) 535 [M + Na Mp 81。C。
实施例 9制备双 {[(1H-吲哚 -3-基) -乙酸甲酯】 -2-基 }-(3,4-二甲氧基苯基) -甲垸(M9)
按照实施例 1的方法, 从 1 g (5.3 mmol ) 吲哚 -3-乙酸, 30 ml甲醇和 450 mg (2.7 mmol) 3,4-二甲氧基苯甲醛得到 1.4 g (99%)目标化合物, 为无色粉末。 IR (KBr) 3624, 3355, 3054, 3002, 2951 , 2835, 2712, 2591 , 2363, 2033, 1921 , 1888, 1719, 1591, 1513, 1493, 1456, 1270, 1026, 935, 851, 807, 742, 726, 676, 592, 549, 479。 ΧΗΝΜΚ (300Μ DMSO-d6): δ/ppm = 10.65 (s 2Η), 7.45 (d
2Η), 7.00 (t
1Η), 6.05 (s 1Η), 3.77 (s 3Η), 3.67 (s 3Η), 3.66(s 3Η), 3.48(s 6Η)。 13C NMR (75M DMSO-d6): δ/ppm = 172.4, 149.2, 148.3, 136.4, 136.2, 136.0, 135.8, 133.3, 128.4, 121.5, 121.0, 1 19.2, 1 18.5, 1 13.0, 1 12.2, 1 1 1.7, 105.2, 56.0, 51.9, 29.7。 FAB-MS (m/e) 549 [M + Na Mp 173 °C. 实施例 10制备双 {[(1H-吲哚 -3-基) -乙酸甲酯】 -2-基 }-(3,4-亚甲二氧基苯基) -甲垸(M10) 按照实施例 1的方法, 从 lg (5.3 mmol ) 吲哚 -3-乙酸, 30 ml甲醇和 405 mg (2.7 mmol) 3,4-亚甲二氧基苯甲醛得到 1.0 g (;73%)目标化合物,为微黄色固体。 IR (KBr) 3742, 3386, 3056, 2950, 2898, 2361 , 1726, 1618, 1558, 1502,1487, 1459, 1437, 1340, 1310, 1237, 1 167, 1036, 928, 851, 810, 744, 590, 547, 479。 1腿 MR (300M DMSO-d6): δ/ppm = 10.63 (s
2Η), 6.99 (t
), 6.03(s 1Η), 5.99(s 1Η),3.67 (s 4Η), 3.48 (s 6Η)。 13C NMR (75Μ DMSO-d6): δ/ppm = 172.3, 147.9, 146.5, 136.1 , 136.0, 135.9, 134.8, 128.3, 122.0, 121.5, 1 19.2, 1 18.6, 1 1 1.7, 109.3, 108.6, 105.4, 101.4。 FAB-MS (m/e) 523 [M + Na]+。 Mp 72 °C。
实施例 11制备双 {[(1H-吲哚 -3-基) -乙酸甲酯】 -2-基 }-(2-羟基 -4-羧基苯基) -甲垸(Mil) 按照实施例 1的方法, 从 lg (5.3 mmol ) 吲哚 -3-乙酸, 30 ml甲醇和 450 mg (2.7 mmol) 2-羟基 -4-羧基苯甲醛得到 1.0 g (;70%)目标化合物, 为淡紫色固体。 IR (KBr) 3858, 3742, 3672, 3391 , 3058, 2953, 2361 , 1718, 1617, 1558, 1489, 1458, 1437, 1342, 1273, 1206, 1083, 1018, 928, 840, 803, 744, 672, 547。 ^MR (300M DMSO-d6): δ/ppm = 10.63 (s 2Η),
9.90(s 1H), 8.39(s 1H), 7.59(d J=1.8Hz 1H), 7.45(d J=7.8Hz 2H), 7.34 (d J=7.1Hz 2H), 7.29(d J=2.1Hz 1H), 7.05 (t J=6.9Hz J=8.7Hz 2H), 6.99 (t J=8.7Hz J=6.9Hz 2H), 6.93 (s 1H), 6.09 (s 1H), 3.68 (s 4H), 3.46 (s 6H)。 13C NMR (75M DMSO-d6): δ/ppm = 191.5, 172.2, 172.1 , 160.3, 136.2, 136.1 , 135.9, 135.7, 130.2, 128.3, 121.6, 1 19.3, 1 18.6, 1 17.7, 1 13.0, 1 1 1.7, 105.5, 51.9, 29.7。 FAB-MS (m/e) 549 [M + Na]+。 Mp 72。C。 本发明通式 lb化合物 (El-Ell)的制备方法
实施例 12制备双 {[(1H-吲哚 -3-基) -乙酸乙酯】 -2-基 }-(4-羟基苯基) -甲烷(E1)
将 lg (5.3 mmol ) 吲哚 -3-乙酸溶于 30 ml 乙醇,往里滴加 l ml浓硫酸和 320 mg (2.7 mmol) 对羟基苯甲醛, 室温反应 48 h, 减压浓縮除去溶剂, 残留物经柱层析分离得到 1.3 g (94%)标题化合物, 为淡紫红色固体。 IR (KBr) 3742, 3388, 3057, 2981 , 2362, 1889, 1714, 1614, 1595, 1559, 1513, 1489, 1459, 1370, 1338, 1307, 1267, 1223, 1 175, 101 1, 1029, 932, 833, 744, 676, 602, 517。 i iNMR (300M DMSO-d6): δ/ppm = 10.6 (s 2Η), 9.73(s 1Η), 7.45 (d
2H), 6.02 (s 1H), 4.03(q J=7.2Hz J=7.4Hz 4H), 3.72 (s 4H), 1.07 (t J=7.2Hz J=7.2Hz 6H)。 13C NMR (75M DMSO-d6): δ/ppm = 171.9, 156.5, 136.4, 135.8, 131.1 , 129.7, 128.3, 121.4, 1 19.2, 1 18.6, 1 15.5, 1 1 1.6, 105.3, 60.5, 65.39, 30.1, 14.4。 FAB-MS (mle) 533 [M + Na]+。 Mp 69。C。 实施例 13制备双 {[(1H-吲哚 -3-基) -乙酸乙酯】 -2-基 }-(4-氯苯基) -甲垸(E2)
将 1 g (5.3 mmol ) 吲哚 -3-乙酸溶于 30 ml 乙醇, 往里滴加 1 ml浓硫酸和 380 mg (2.7 mmol) 对氯苯甲醛, 室温反应 48 h, 减压浓縮除去溶剂, 残留物用乙酸乙酯溶解, 得到的溶液先用饱和 NaHC03洗 3次, 再用和饱和 NaCl水溶液洗 3次, 合并的乙酸乙 酯层用无水 Na2S04干燥过夜, 过滤, 滤液减压浓縮除去溶剂。 残留物通过乙酸乙酯-石 油醚体系重结晶, 得到 1.4 g C98%)标题化合物, 为无色针状晶体。 IR (KBr) 3859, 3742, 3672, 3649, 3354, 3057, 2981 , 2935, 2361 , 1714, 1653, 1620, 1558, 1506, 1489, 1459, 1402, 1369, 1309, 1274, 1 162, 1095, 1031 , 1015, 930, 848, 806, 744, 665, 548, 499, 474。 iHNMR (300M DMSO-d6): δ/ppm = 10.7 (s 2H), 7.46 (d J=7.5Hz 2H), 7.40 (d J=8.4Hz 2H), 7.34(d J=7.8Hz 2H), 7.16(d J=8.4Hz 2H), 7.07 (t J=6.9Hz J=8.4Hz 2H), 7.02 (t J=6.9Hz J=8.4Hz 2H), 6.14 (s 1H), 3.93(q J=6.6Hz J=6.9Hz J=8.4Hz 4H), 3.68 (s 4H), 1.05(t J=7.2Hz J=7.4Hz 6H)。 13C NMR (75M DMSO-d6): δ/ppm = 171.8, 140.1 , 136.1 , 136.0, 135.5, 135.3, 131.1 , 130.7, 128.8, 128.2, 121.7, 1 19.3, 1 18.7, 1 1 1.7, 105.8。 FAB-MS (m/e) 551 [M + Na]+。
实施例 14制备双 {[(1H-吲哚 -3-基) -乙酸乙酯】 -2-基 }-(4-硝基苯基) -甲烷(E3) 按照实施例 12 的方法,从 l g (5.3 mmol ) 吲哚 -3-乙酸, 30 ml 乙醇和 410 mg (2.7 mmol)对硝基苯甲醛得到 1.2 g (83%)标题化合物, 为淡黄色固体。 IR (KBr) 3858, 3741 ,
3672, 3649, 3384, 3058, 2981 , 2361 , 1718, 1653, 1599, 1558, 1520, 1490, 1458, 1369, 1347, 1268, 1240, 1 177, 1 104, 1029, 932, 851, 817, 744, 660, 492。 ^MR (300M DMSO-d6): δ/ppm = 10.7 (s 2Η), 8.23 (d
2Η), 7.36(d
2Η), 6.34 (s 1Η), 3.94(q
4Η), 3.78 (s 4H),1.05(t J=7.2Hz J=6.9Hz 6H)。 13C NMR (75M DMSO-d6): δ/ppm = 171.7, 149.0, 146.9, 136.2, 134.7, 130.2, 128.2, 124.0, 121.8, 1 19.4, 1 18.8, 1 1 1.8, 106.2, 60.5, 30.1 , 14.5。 FAB-MS (mle) 562 [M + Na]+, Mp 49 °C o 实施例 15制备双 {[(1H-吲哚 -3-基) -乙酸乙酯】 -2-基 }-(3-硝基苯基) -甲垸(E4)
按照实施例 12 的方法, 从 lg (5.3 mmol ) 吲哚 -3-乙酸, 30 ml 乙醇和 410 mg (2.7 mmol) 间硝基苯甲醛得到 1.2 g (;83%)标题化合物, 为淡黄色固体。 IR (KBr) 3860, 3742,
3673, 3650, 3380, 3060, 2982, 2362, 1717, 1653, 1619, 1558, 1530, 1507, 1458, 1351 , 1268, 1239, 1 177, 1098, 1029, 931 , 848, 805, 744, 674, 546。 ^MR (300M DMSO-d6): δ/ppm =
10.72 (s 2Η), 8.17(m 1Η), 7.99(s 1Η), 7.65 (d
2H), 7.47 (d J=7.8Hz 2H), 7.34(d J=7.8Hz 2H), 7.07 (t J=6.9Hz J=7.8Hz 2H), 7.01 (t J=6.9Hz J=7.8Hz 2H), 6.33 (s 1H), 3.92 (q J=7.2Hz J=7.2Hz J=7.2Hz 4H), 3.70 (s 4H), 1.02 (t J=7.2Hz J=7.2Hz 6H)。13C NMR (75M DMSO-d6): δ/ppm = 171.7, 148.4, 143.5, 136.1 , 135.7, 134.7, 130.4, 128.2, 123.4, 122.4, 121.8, 1 19.4, 1 18.8, 1 1 1.8, 106.1, 60.5, 30.0, 14.34。 FAB-MS (mle) 562 [M + Na]+o Mp 62 °C。
实施例 16制备双 {[(1H-吲哚 -3-基) -乙酸乙酯】 -2-基 }-(3-甲氧基 -4-羟基苯基) -甲烷(E5) 按照实施例 12的方法, 从 l g (5.3 mmol ) 吲哚 -3-乙酸, 30 ml 乙醇和 410 mg (2.7 mmol) 3-甲氧基 -4-羟基苯甲醛得到 1.1 g (76%)标题化合物, 为紫红色固体。 IR (KBr) 3859, 3742, 3673, 3649, 3624, 3372, 3057, 2979, 2361 , 1716, 1653, 1606, 1558, 1514, 1458, 1370, 1272, 1234, 1 176, 1030, 935, 743, 624, 552。 ^MR (300M DMSO-d6): δ/ppm = 10.60 (s 2Η), 9.78 (s 1Η), 8.94(s 1Η), 7.43 (d
2H), 7.34 (d J=7.8Hz 2H), 7.05 (t J=6.9Hz J=6.9Hz 2H) 6.98 (t J=7.2Hz J=7.2Hz 2H), 6.83 (d J= 1.8Hz 2H), 6.73(d J=8.1Hz 1H), 6.59 (dd J=1.5Hz, J=8.1Hz), 5.99 (s 1H), 4.04 (q J=7.2Hz J=7.2Hz J=7.2Hz 4H), 3.65 (s 4H), 3.61 (s 3H), 1.06 (t J=7.2Hz J=7.2Hz 6H)。 13C NMR (75M DMSO-d6): δ/ppm = 192.0, 171.9, 148.5, 149.2, 136.5, 135.9, 132.5, 128.5, 122.4, 1 19.6, 1 18.5, 1 16.2, 1 16.0, 1 14.2,
1 13.0, 105.2, 60.5, 56.1, 30.0, 14.4。 FAB-MS (mle) 563 [M + Na]+o Mp 58。C。 实施例 17制备双 {[(IH-吲哚 -3-基) -乙酸乙酯】 -2-基 }-(3,5-二甲氧基 -4-羟基苯基) -甲垸 (E6)
将 1 g (5.3 mmol ) 吲哚 -3-乙酸溶于 30 ml 乙醇, 往里滴加 1 ml浓硫酸和 490 mg (2.7 mmol) 3,5-二甲氧基 -4-羟基苯甲醛室温反应 48 h, 反应液中析出大量固体, 过滤得 到 1.3 g (85%)标题化合物, 为淡粉色颗粒。 IR (KBr) 3859, 3742, 3672, 3335, 3056, 2980, 2937, 2841 , 2361 , 1708, 1615, 1517, 1458, 1426, 1370, 1319, 1217, 1 166, 1 1 17, 1028, 921 , 835, 808, 740, 703, 660, 589, 466。 ^MR (300M DMSO-d6): δ/ppm = 10.61 (s 2Η), 8.32 (s 1Η), 7.42 (d
2H), 7.35 (d J=7.8Hz 2H), 7.05 (t J=6.9Hz J=8.4Hz 2H), 6.98 (t J=7.5Hz J=7.5Hz 2H), 6.58 (s 2Hz), 5.98 (s 1H), 3.93 (q J=6.9Hz J=7.2Hz J=7.2Hz 4H), 3.66 (s 6H), 3.59 (s 4H), 1.06 (t J=6.9Hz J=7.2Hz 6H)。 13C NMR (75M DMSO-d6): δ/ppm = 171.9, 148.4, 136.5, 135.9, 135.8, 130.7, 128.5, 121.3, 1 19.1, 1 18.5, 1 1 1.7, 106.9, 105.2, 60.6, 56.5, 30.0, 14.4。 FAB-MS (mle) 593 [M + Na]+。
实施例 18制备双 {[(IH-吲哚 -3-基) -乙酸乙酯】 -2-基 }-(3,4-二羟基苯基) -甲垸(E7)
按照实施例 12的方法, 从 1 g (5.3 mmol ) 吲哚 -3-乙酸, 30 ml 乙醇和 370 mg (2.7 mmol) 3,4-二羟基苯甲醛得到 1.1 g (78%)标题化合物, 为砖红色固体。 IR (KBr) 3859, 3742, 3672, 3649, 3382, 3057, 2981 , 2361 , 1712, 1653, 1613, 1558, 1519, 1459, 1370, 1338, 1279, 1 183, 1 1 10, 1029, 951, 743, 586。 1腿 MR (300M DMSO-d6): δ/ppm = 10.61 (s 2Η), 8.86 (s 1Η), 8.80 (s 1Η), 7.57 (d
实施例 19制备双 {[(1H-吲哚 -3-基) -乙酸乙酯】 -2-基 }-(4-甲氧基苯基) -甲垸(Ε8)
按照实施例 12的方法, 从 lg (5.3 mmol ) 吲哚 -3-乙酸, 30 ml 乙醇和 410 mg (3.0 mmol) 4-甲氧基苯基甲醛得到 1.3 g (;89%)标题化合物, 为淡蓝色固体。 IR (KBr): 3859, 3742, 3672, 3649, 3375, 3057, 2980, 2934, 2804, 2361 , 1717, 1653, 1619, 1591 , 1551 , 1510, 1459, 1370, 1306, 1273, 1240, 1 176, 1 130, 1029, 956, 847, 743, 679, 600。 1腿 MR (300M DMSO-d6): δ/ppm = 10.67 (s 2Η), 8.98 (s 1Η), 7.49 (d
2Η),
), 6.62(d
/=6.9Ηζ
J=7.2Hz 4H), 3.75 (s 4H), 3.72 (s 3H), 1.10 (t J=7.2Hz J=7.2Hz 6H)。 13C NMR (75M DMSO-d6): δ/ppm = 171.9, 147.0, 146.9, 146.8, 136.4, 136.0, 133.5, 128.3, 121.5, 119.5, 119.2, 118.6, 116.1, 112.6, 111.7, 105.4, 60.5, 56.2, 27.3, 14.5。 FAB-MS (mle) 563 [M + Na]+。 Mp 101 °C。
实施例 20制备双 {[(1H-吲哚 -3-基) -乙酸乙酯】 -2-基 }-(3,4 -二甲氧基苯基) -甲垸(E9) 按照实施例 12的方法, 从 1 g (5.3 mmol ) 吲哚 -3-乙酸, 30 ml 乙醇和 450 mg (2.7 mmol) 3,4-二甲氧基苯甲醛得到 1.2 g (80%)标题化合物, 为无色粉末。 IR (KBr): 3742, 3361, 3057, 2978, 2933, 2905, 2836, 2362, 1887, 1719, 1592, 1550, 1514, 1458, 1414, 1369, 1313, 1267, 1146, 1100, 1030, 938, 848, 743, 678, 600, 551, 477, 437。 ^MR (300M DMSO-d6): δ/ppm = 10.64 (s 2Η), 7.45 (d
2Η), 7.09 (t
1Η), 6.06 (s 1Η), 3.95 (q
4Η), 3.74 (s 4Η), 3.65 (s 3Η), 3.63(s 3Η), 1.07 (t
6Η)。 13C NMR (75Μ DMSO-d6): δ/ppm = 171.9, 149.2, 148.3, 136.4, 136.0, 133.3, 128.5, 121.4, 121.1, 119.1, 118.6, 113.1, 112.2, 111.7, 105.3, 60.5, 56.0, 30.0, 14.4。 FAB-MS ) 577 [M + Na]+。 Mp 79。C。
实施例 21制备双 {[(1H-吲哚 -3-基) -乙酸乙酯】 -2-基 }-(3,4 -亚甲二氧基苯基) -甲垸(E10) 按照实施例 12的方法, 从 1 g (5.3 mmol ) 吲哚 -3-乙酸, 30 ml 乙醇和 405 mg (2.7 mmol) 3,4-亚甲二氧基苯甲醛得到 800 mg (;55%)标题化合物, 为无色粉末。 IR (KBr): 3742, 3649, 3357, 3060, 2982, 2934, 2897, 2778, 2362, 1867, 1715, 1619, 1558, 1502, 1448, 1458, 1447, 1367, 1343, 1309, 1250, 1154, 1098, 1035, 930, 863, 815, 789, 744, 666, 627, 592, 551, 481 ο
2H), 7.37 (d J=7.8Hz 2H), 7.09 (t J=7.2Hz J=7.5Hz 2H), 6.90 (d J=7.1Hz 1H), 6.76 (s 1H), 6.68 (d J=7.8Hz 1H), 6.07 (s 1H), 6.00 (s 2H), 3.96 (q J=6.9Hz J=7.2Hz J=6.9Hz 4H), 3.68 (s 4H), 1.08 (t J=7.2Hz J=6.9Hz 6H)。 13C NMR (75M DMSO-d6): δ/ppm = 171.9, 147.9, 146.5, 136.1, 136.0, 135.9, 134.9, 128.3, 122.0, 121.5, 119.2, 118.6, 111.7, 111.7, 109.4, 108.6, 105.5, 105.5, 101.560.6, 30.0, 14.5, 14.4。 FAB-MS (mle) 561 [M+Na]+。 Mp 129。C。
实施例 22制备双 {[(1H-吲哚 -3-基) -乙酸乙酯】 -2-基 }-(2-羟基 -4-羧基苯基) -甲垸(E11) 按照实施例 12的方法, 从 l g (5.3 mmol ) 吲哚 -3-乙酸, 30 ml 乙醇和 450 mg (2.7 mmol) 2-羟基 -4-羧基苯甲醛得到 1.0 g (67%)标题化合物,为蓝紫色固体。 IR (KBr): 3859, 3742, 3673, 3650, 3370, 3059, 2982, 2362, 1713, 1616, 1558, 1489, 1458, 1370, 1338, 1304,
1272, 1 182, 1099, 1029, 929, 840, 803, 743, 673, 592, 548, 437。 'HNMR (300M DMSO-d6): δ/ppm = 10.64 (s 2H), 7.58 (d J=2.1Hz 1H), 7.45 (d J=7.8Hz 2H), 7.33(d J=7.8Hz 2H), 7.28(dd J=7.8Hz J=2.1Hz 1H), 7.06 (t J=6.6Hz J=6.9Hz 2H), 6.99 (t J=6.6Hz J=6.9Hz 2H), 6.92 (d J=7.8Hz 1H), 6.09 (s 1H), 3.94(q J=4.2Hz J=5.1/=4.2HHz 4H), 3.66 (s 4H), 1.04 (t J=6.9Hz J=5.1Hz 6H)。 13C NMR (75M DMSO-d6): δ/ppm = 172.1 , 171.8, 160.4, 136.1 , 135.9, 131.6, 130.2, 128.3, 121.5, 1 19.2, 1 18.6, 1 17.6, 1 13.4, 1 1 1.7, 105.5, 65.4, 60.5, 30.1 , 14.4。 FAB-MS (m/e) 577 [M + Na]+。 Mp 103 0C。 本发明通式 Ic化合物 (Cl-Cll)的制备方法
实施例 23制备双 {[(1H-吲哚 -3-基) -乙酸】-2-基}-(4-羟基苯基) -甲垸(C1)
348 mg (2 mmol) 吲哚 -3-乙酸和 122 mg (1 mmol) 对羟基苯甲醛溶于 10 ml无水四 氢呋喃, 滴加 0.1 ml浓硫酸, 室温反应 12 h, 减压浓縮至干, 残留物用 30 ml 乙酸乙酯 溶解, 得到的溶液用饱和 NaHC03水溶液洗至乙酸乙酯层为中性, 水层用饱和 KHS04 调节 pH值为 2, 用乙酸乙酯萃取 3次, 每次用 30 ml 乙酸乙酯。 合并的乙酸乙酯层用 无水 Na2S04干燥过夜, 过滤, 滤液减压浓縮至干, 得到 300 mg (58%) 标题化合物。 IR (KBr): 3389, 3054, 1707, 161 1, 1512, 1458, 1341 , 1230, 1 174, 1 103, 1043, 835, 745, 604, 517, 438 o iHNMR (300M DMSO-d6): δ/ppm = 12.15 (s 2H), 10.61(s 2H), 9.31(s 1H), 7.45 (d J=7.5Hz 2H ), 7.32 (d J=7.8Hz 2H ), 7.03 (m 6H), 6.69 (d J=8.7Hz 2H ), 6.02 (s 1H), 3.59 (s 4H)。 13C NMR (75M DMSO-d6): δ/ppm = 173.8, 156.6, 136.5, 136.0, 131.3, 129.6, 128.4, 121.4, 1 19.1, 1 18.7, 1 15.5, 1 1 1.5, 106.0, 30.3。 FAB-MS (m/e) 453 [M - H]—, Mp 100。C。 实施例 24制备双 {[(1H-吲哚 -3-基) -乙酸】-2-基}-(4-氯苯基) -甲垸(C2)
按照实施例 23的方法, 从 348 mg (2 mmol) 吲哚 -3-乙酸和 140 mg (1 mmol) 对氯 苯甲醛得到 350 mg (94%) 标题化合物。 IR (KBr): 3427, 2924, 2361 , 1706, 1627, 1489, 1458, 1225, 1094, 1014, 744。 ^MR (300M DMSO-d6): δ/ppm = 1 1.06(s 2Η), 7.48 (d
2Η), 6.98 (m 4Η ), 6.15 (s 1Η), 3.57 (s 4H)。 13C NMR (75M DMSO-d6): δ/ppm = 174.1 , 140.5, 136.1 , 135.5, 131.7, 130.5, 128.6, 128.5, 121.4, 1 19.0, 1 18.9, 1 1 1.5, 106.8, 31.0。 FAB-MS (m/e) 471 [M - H]", Mp 106。C。 实施例 25制备双 {[(1H-吲哚 -3-基) -乙酸】-2-基}-(4-硝基苯基) -甲垸(C3)
348 mg (2 mmol) 吲哚 -3-乙酸和 151 mg (1 mmol) 对硝基苯甲醛溶于 10 ml无水四 氢呋喃, 滴加 0.1 ml浓硫酸, 室温反应 12 h, 减压浓縮至干, 残留物用 30 ml 乙酸乙酯
溶解, 得到的溶液用饱和 NaHC03水溶液洗至乙酸乙酯层为中性, 水层用饱和 KHS04 调节 pH值为 2, 用乙酸乙酯萃取 3次, 每次用 30 ml 乙酸乙酯。 合并的乙酸乙酯层用 无水 Na2S04干燥过夜, 过滤, 滤液减压浓縮至干, 得到 300 mg (60%) 标题化合物。 IR (KBr): 3402, 3058, 2361, 1708, 1600, 1519, 1457, 1411, 1346, 1239, 1174, 1043, 1015, 852, 745, 607, 430。 iHNMR (500M DMSO-d6): δ/ppm = 10.72 (s 2H), 8.2(d J=20.0Hz 2H), 7.45 (d J=25.0Hz 2H ), 7.40 (d J=25.0Hz 2H ), 7.34 (d J=25.0Hz 2H ), 7.09 (t J=5.0Hz J=10.0Hz 2H), 7.01 (t J=5.0Hz J=10.0Hz 2H), 6.32 (s IH ), 3.65 (s 4H)。 13C NMR (125M DMSO-d6): δ/ppm = 173.5, 149.2, 146.8, 136.2, 134.7, 130.1,128.3, 123.9, 121.8, 119.3, 118.9, 111.7, 106.8, 30.2。 FAB-MS (m/e) 497 [M - H]—, Mp 73 0C。
实施例 26制备双 {[(IH-吲哚 -3-基) -乙酸】-2-基 }-(3-硝基苯基) -甲烷(C4)
按照实施例 23的方法,从 348 mg (2 mmol) 吲哚 -3-乙酸和 151 mg (1 mmol) 间硝基 苯甲醛得到 300 mg (60%) 标题化合物。 IR (KBr): 3403, 3058, 2361, 1707, 1529, 1458, 1349, 1236, 1098, 1043, 926, 805, 743, 605, 438o ^MR (500M DMSO-d6): δ/ppm = 12.2(s 2Η), 10.73 (s 2Η), 8.17(d J=5.0Hz 1H), 8.15 (s 1H), 7.64 (s 2H), 7.51 (d J=10.0Hz 2H ), 7.3 (d J=10.0Hz 2H ), 7.08 (t J=5.0Hz J=10.0Hz 2H), 7.02 (t J=5.0Hz J=10.0Hz 2H), 6.48 (s IH ), 3.68 (s 4H)。 13C NMR (125M DMSO-d6): δ/ppm = 173.6, 148.4,143.7, 136.3, 135.6, 134.8, 130.3, 128.4, 123.5, 122.3, 121.8, 121.5, 119.3, 111.8, 106.8, 30.2。 FAB-MS (m/e) 497 [M-H]", Mp 74 0C。
实施例 27制备双 {[(IH-吲哚 -3-基) -乙酸】-2-基 }-(3-甲氧基 -4-羟基苯基) -甲垸(C5)
按照实施例 23的方法,从 348 mg (2 mmol) 吲哚 -3-乙酸和 152 mg (1 mmol) 3-甲氧 基 -4-羟基苯甲醛得到 200 mg (40%) 标题化合物。 IR (KBr): 3420, 2932, 2361, 1708, 1617, 1514, 1459, 1272, 1030, 744, 598, 440。 ^MR (300M DMSO-d6): δ/ppm = 12.1 l(s 2Η), 10.60 (s 2Η), 8.6(s 1Η), 7.43 (d
4H ), 7.39 (d J=7.5Hz 4H ), 7.05 (t J=6.9Hz J=7.8Hz 2H), 6.97 (t J=7.2Hz J=7.2Hz 2H), 6.83 (s IH ), 6.21 (d J=7.8Hz IH ), 6.58 (d J=8.4Hz IH ), 6.01 (s 1H), 3.65 (s 4H), 3.56 (s 3H)。 13C NMR (75M DMSO-d6): δ/ppm = 173.8, 148.0, 136.5, 136.0, 128.5, 121.3, 119.0, 118.7, 115.7, 111.5, 105.7, 56.1, 30.2。 FAB-MS (m/e) 496 [M - H]—, Mp 110 0C。
实施例 28制备双 {[(IH-吲哚 -3-基) -乙酸】-2-基 }-(3,5-二甲氧基 -4-羟基苯基) -甲烷(C6) 按照实施例 23的方法, 从 348 mg (2 mmol) 吲哚 -3-乙酸和 181 mg (1 mmol) 3,5-二
甲氧基 -4-羟基苯甲醛得到 300mg(57%) 标题化合物。 IR (KBr): 3400, 2939, 2360, 1707, 1618, 1515, 1458, 1328, 1215, 1111, 838, 743,603 ^MR (300M DMSO-d6): δ/ppm = 10.61 (s 2H), 7.43 (d J=7.8Hz 2H ), 7.33(d J=7.8Hz 2H ), 7.07 (t J=7.8Hz J=6.9Hz 2H), 6.97 (t J=7.8Hz J=6.9Hz 2H), 6.56 (s 2H), 5.98 (s 1H), 3.63 (s 6H), 3.53 (s 4H)。 13C NMR (75M DMSO-d6): δ/ppm = 173.7, 148.4, 136.4, 136.0, 135.0, 130.9, 128.5, 121.3, 119.0, 118.6, 111.6, 106.9, 105.8,56.5,30.2。 FAB-MS (m/e) 527 [M - H]", Mp 104。C。 实施例 29制备双 {[(1H-吲哚 -3-基) -乙酸】-2-基 }-(3,4-二羟基苯基) -甲垸(C7)
按照实施例 23的方法, 从 348 mg (2 mmol) 吲哚 -3-乙酸和 167 mg (1.2 mmol) 3,4- 二羟基苯甲醛得到 200 mg (40%)标题化合物。 IR (KBr): 3421, 2361, 1706, 1621, 1519, 1457, 1189, 745, 440。 i iNMR (300M DMSO-d6): δ/ppm = 10.60 (S 2Η), 8.81 (S 1Η), 8.74 (S 1Η), 7.45 (d
2H ), 7.32 (d J=7.8Hz 2H ), 7.06 (t J=7.9Hz J=6.5Hz 2H), 6.98 (t J=7.5Hz J=7.2Hz 2H), 6.65 (d J=8.1Hz 1H), 6.34 (S 1H), 6.21 (S 1H), 5.98 (S 1H), 3.61 (S lH 13C NMR (75M DMSO-d6): δ/ppm = 173.8, 145.5, 144.5, 136.6, 136.0, 131.9, 128.4, 121.4, 119.5, 119.0, 118.7, 116.2, 115.8, 111.5, 105.9,30.3。 FAB-MS (mle) 496 [M - H]—, Mp 790C。 实施例 30制备双 {[(1H-吲哚 -3-基) -乙酸】-2-基 }-(4-甲氧基苯基) -甲垸(C8)
按照实施例 23的方法, 从 348 mg (2 mmol) 吲哚 -3-乙酸和 152 mg (1.1 mmol) 4-甲 氧基苯甲醛得到 200 mg (40%)标题化合物 , IR (KBr): 3399, 3057, 2973, 2361, 1708, 1618, 1511, 1457, 1272, 1130, 1022, 878, 745, 605, 439。 1腿 MR (300M DMSO-d6): δ/ppm = 10.6
1Η), 6.01(s 1Η), 3.73(s 3Η), 3.61 (s 4Η)。 13C NMR (75Μ DMSO-d6): δ/ppm =173.7, 146.9, 136.4, 136.0, 133.7, 128.3, 121.4, 119.3, 119.1, 118.7, 112.8, 111.5, 106.0, 56.2, 30.3。 FAB-MS (mle) 496 [M - Η]—, Mp 1030C。 实施例 31制备双 {[(1H-吲哚 -3-基) -乙酸】-2-基 }-(3,4-二甲氧基苯基) -甲垸(C9)
按照实施例 23的方法, 从 348 mg (2 mmol) 吲哚 -3-乙酸和 179 mg (1.1 mmol) 3,4- 二甲氧基苯甲醛得到 200 mg (38%) 标题化合物。 IR (KBr): 3413, 2935, 2360, 1709, 1621, 1513, 1459, 1414, 1264, 1142, 1023, 744, 601, 439。 ^MR (300M DMSO-d6): δ/ppm = 12.19 (s 2Η), 10.67 (s 2Η), 7.47 (d 2H ), 7.32 (d J=7.2Hz 2H ), 7.06 (t J=6.9Hz
J=7.2Hz 2H), 6.99 (t J=7.2Hz J=6.9Hz 2H), 6.91 (m 2H), 6.71 (d J=7.2Hz 1H), 6.15(s 1H), 5.81(s 1H), 3.79(s 4H), 3.68 (s 3H), 3.53 (S 3H)。 13C NMR (75M DMSO-d6): δ/ppm = 173.8, 149.2, 148.2, 136.3, 136.0, 133.5, 128.5, 121.4, 120.8, 1 10.1 , 1 18.7, 1 13.0, 1 12.1 , 1 1 1.6, 106.0, 56.0, 30.2。 FAB-MS (m/e) 508 [M - H]—, Mp 81。C。 实施例 32制备双 {[(1H-吲哚 -3-基) -乙酸】-2-基}-(3,4 -亚甲二氧基苯基) -甲烷(C10)
按照实施例 23的方法, 从 348 mg (2 mmol) 吲哚 -3-乙酸和 151 mg (1 mmol) 3,4-亚 甲二氧基苯甲醛得到 200 mg (40%) 标题化合物。 IR (KBr): 3406, 2902, 2360, 1707, 1489,
1456, 1242, 1038, 927, 810, 744, 600, 427。 i iNMR (300M DMSO-d6): δ/ppm = 12.07 (s 2Η), 10.64 (s 2Η), 7.45 (d
2H ), 7.33 (d J=7.8Hz 2H ), 7.06 (t J=7.2Hz J=7.5Hz 2H), 6.98 (t J=7.2Hz J=7.5Hz 2H), 6.84 (d J=7.8Hz 1H), 6.71 (s 1H), 6.63 (d J=7.8Hz 1H), 6.05 (s 1H), 5.98(s 1H), 3.59(s 4H)。 13C NMR (75M DMSO-d6): δ/ppm = 173.7, 147.8, 146.4, 136.0, 135.0, 128.4, 121.8, 121.5, 1 19.1, 1 18.7, 1 1 1.6, 109.3, 108.5, 106.1, 101.4, 30.2。 FAB-MS (m/e) 497 [M - H]—, Mp 81。C。 实施例 33制备双 {[(1H-吲哚 -3-基) -乙酸】-2-基 }-(2-羟基 -4-羧基苯基) -甲烷(C11)
按照实施例 23的方法, 从 348 mg (2 mmol) 吲哚 -3-乙酸和 166 mg (1 mmol) 2-羟基
-4-羧基苯甲醛得到 200 mg (40%) 标题化合物。 IR (KBr): 3416, 3056, 2360, 1701 , 1491,
1457, 1299, 1210, 745, 672, 601, 420。 i iNMR (300M DMSO-d6): δ/ppm = 10.52 (s 2Η), 7.52 (d /= 1.8Hz 1H ), 7.42 (d J=7.8Hz 2H ), 7.29 (d J=7.8Hz 2H ), 7.23 (dd J=7.1Hz J=1.81Hz 1H), 7.03 (m 4H), 6.87 (d /=7.8Hz 1H), 6.05 (s 1H), 3.54 (s 4H)。 13C NMR (75M DMSO-d6): δ/ppm = 174.0, 172.1 , 160.3, 135.9, 135.7, 131.6, 129.9, 128.2, 121.9, 1 19.5, 1 18.7, 1 17.7, 1 13.3, 1 1 1.6, 106.0, 30.1。 FAB-MS (m/e) 495 [M - H]—, Mp 109。C。 实验例 1 本发明化合物 Ml-Mll, El-Ell, Cl-Cll的体外细胞毒性
本发明的 Ml-Mll, El-Ell或 Cl-Cll之一的化合物均分别用含 0.1% DMSO的细 胞培养液配制。 共使用了 S 180(小鼠肉瘤细胞)、 C6(大鼠脑胶质瘤细胞)、 K562(慢性粒 细胞白血病细胞)、 HepG2(肝细胞癌细胞)和 MCF-7(人乳腺癌细胞 )5株肿瘤细胞。
分别将生长状态良好处于对数生长期的 HepG2、 MCF-7、 S 180、 C6和 K562细胞按 照 5 X 104个 /mL 的密度接种于 96孔板, 每孔 100 μ1。 在 37 °C、 5% C02 培养箱中培养 4小时, 按预设的浓度梯度 400μΜ、 40μΜ、 10μΜ、 5 μΜ、 1 μΜ、 100 ηΜ、 5 ηΜ禾卩 1 ηΜ 分别加入经灭菌处理的本发明的化合物, 采用阿霉素作对照。 继续培养 48小时后, 每
孔加 25 μΐ浓度为 5 mg/mL的 MTT溶液, 置于 37 °C孵育 4小时, 小心除去上清液 (悬 浮细胞经离心后除去上清液)后每孔加入 100 μΐ DMSO (二甲基亚砜), 振荡约 15 min溶 解沉淀。 立即于酶标仪上 570 nm波长下测定 O.D. (吸亮度) 值。 计算抑瘤率及 IC5Q。 结 果列入表 1。 结果表明本发明的 M1-M11, E1-E11或 C1-C11之一的化合物对五种肿瘤 细胞都没有明显的细胞毒作用。 表 1 本发明 M1-M11, El-Ell, C1-C11化合物的 IC5。(μΜ)值 化合物 K562 S180 MCF-7 HepG2 C6
Ml 4.3 ± 0.62 4.38 ± 1.13 3.79 ± 1.64 25.08 ±6.88 3.37±0.18
M2 52.5 ±8.77 57.4 ± 15.2 8.52 ±0.85 92.31 ± 11.74 19.49 ±2.58
M3 38.53 ±3.68 10.47 ±0.52 28.53 ±3.73 151.84± 1.54 20.02 ± 6.23
M4 35.87 ±8.49 21.91 ±9.85 24.78 ±7.31 103.79 ±26.7 34.57 ± 10.09
M5 5.43 ± 1.01 4.06 ±2.76 5.03 ±0.8 43.36 ± 12.25 5.80 ± 1.64
M6 2.25 ± 1.91 1.97 ±0.42 12.61 ±3.85 129.73 ± 1.35 4.36 ±0.64
M7 5.18± 1.36 6.73 ± 0.64 9.04 ±2.61 11.05 ±5.44 7.02 ±0.57
M8 12.03 ±6.53 6.55 ± 1.19 82.55 ± 1.34 16.00 ±2.25 10.16 ±0.66
M9 41.27 ± 1.07 >400 65.19±23.35 203.89 ±94.36 >400
M10 53.1 ±6.22 11.06 ±0.96 34.06 ±2.98 153.59 ± 10.83 102.14 ± 18.64
Mil 52.45 ±7.57 >400 21.9±3.61 114.17 ±23.02 >400
El 3.63 ± 1.94 3.82 ±0.68 2.4 ±0.5 6.62 ± 1.20 4.57 ±0.24
E2 2.96 ± 1.08 15.6±3.9 20.43 ±4.86 33.34 ± 13.94 13.14 ± 1.48
E3 37.15 ±0.64 >400 24.65 ± 7.4 180.3 ±60.81 30.37 ±2.39
E4 24.73 ±8.13 >400 >400 73.65 ±3.84 19.1±3.48
E5 2.3 ± 0.26 3.81 ±0.8 3.42 ± 1.55 10.77 ± 1.52 3.57±0.28
E6 3.3 ±0.31 >400 26.52 ±3.12 38.18± 11.31 8.86 ±0.24
E7 23.11 ±4.6 3.06 ±0.22 20.03 ±3.9 3.81 ± 1.95 9.16± 1.57
E8 6.03 ±4.43 3.73 ±0.57 31.15 ±3.04 14.16±4.11 2.45 ±0.41
E9 101.9 ±33.42 >400 94.5 ±9.28 129.97 ± 17.2 >400
E10 >400 >400 >400 87.49 ±5.44 >400
Ell 8.44 ± 1.53 >400 >400 47.81 ± 10.01 >400
CI 86.5 ±30.23 >400 >400 >400 >400
C2 11.33 ±3.89 >400 105.98 ±3.95 >400 >400
C3 >400 >400 >400 44.66 ± 14.92 >400
C4 57.52 ± 11.74 >400 >400 >400 >400
C5 113.22 ± 0.4 79.7 ± 3.46 >400 >400 >400
C6 104.33 ± 12.94 >400 >400 >400 >400
C7 132.00 ± 7.97 >400 >400 >400 >400
C8 49.98 ± 3.68 >400 >400 >400 >400
C9 135.4 ± 1.02 >400 >400 >400 >400
CIO 101.87 ± 3.73 >400 >400 >400 >400
Cll 87.85 ± 9.66 >400 >400 >400 >400 阿霉素 0.17 ± 0.06 0.33 ± 0.13 0.53 ± 0.15 1.19 ± 0.35 0.91±0.16 n = 6 o 实验例 2 本发明 Ml-Mll , El-Ell, Cl-Cll化合物的体内抗肿瘤活性
测定前将本发明的 Ml-Mll , El-Ell或 Cl-Cll之一的化合物分别加吐温 80助溶, 溶于生理盐水。 无菌条件下取接种于 ICR小鼠 7-10天的 S18Q肉瘤, 加入适量生理盐水 配制成瘤细胞悬液, 细胞数为 2x l07/mL, 接种于健康雄性 ICR小鼠前肢腋皮下, 每只 小鼠注射 0.2 ml。 肿瘤接种 24 h后, 治疗组小鼠每日腹腔注射 0.2 ml Ml-Mll, El-Ell 或 Cl-Cll之一的化合物水溶液, 连续给药 7天, 剂量为 0.25 μηιο1/1¾。 空白组小鼠每 日腹腔注射 0.2 ml生理盐水。 以阿霉素 (剂量为 2 μηιοΙ/kgM乍阳性对照。 实验进行至第 8 天, 称小鼠体重, 并剖取各组小鼠的肿瘤称重, 最后统计各组动物的抑瘤率。 实体瘤的 疗效以瘤重抑制百分率表示, 计算如下: 瘤重抑制率%= ( 1-给药组瘤重 /空白组瘤重) x l00%。 以瘤重或百分抑瘤率表示化合物的活性, 数据列入表 2。
实验观察到, 在低于 2 mol/kg剂量下, 阿霉素不显示抗肿瘤作用。 在 2 μηιοΐ/kg 剂量下, 阿霉素虽然显示抗肿瘤作用, 但是在治疗的第四天小鼠即开始死亡, 第五天没 有小鼠存活, 显示致命性毒性。 在存活的 4-5天内, 小鼠显示躁动和不安等神经毒性症 状。相反, 0.25 μηιοΐ/kg剂量下 Ml-Mll, E1-E11和 C1-C11化合物全部显示有效的抗肿 瘤作用。 其中£6,£7,∑8,€1,€2,€8,€10和€11有明显优于阿霉素的抗肿瘤作用, 也 就是说这 8个化合物的抗肿瘤活性比阿霉素强 8倍以上 (阿霉素使用剂量为本发明化合 物剂量的 8倍)。其中 Ml, M6, El, E2, E5, E9, Ell, C4, C5, C6和 C9的活性与阿霉素没 有显著性差异,也就是说这 11个化合物的抗肿瘤活性是阿霉素的 8倍左右。在治疗的 8 天内, Ml-Mll, E1-E11或 C1-C11之一的化合物既没有引起任何小鼠死亡, 即没有致 命性毒性, 也没有引起小鼠出现躁动和不安等神经毒性症状。 因而在体内抗肿瘤方面,
本发明化合物在阿霉素剂量八分之一的用量下即可有效抑制肿瘤生成,在致命性毒性和 神经毒性方面, 本发明化合物也比阿霉素低很多。
表 2 本发明 M1-M11, El-Ell, C1-C11化合物的体内抗肿瘤活性
n = 12。 a)与生理盐水组比 < 0.01。 b)与生理盐水组比 p < 0.01, 与阿霉素组比 p > 0.05 实验例 3 发明人先前研究发现的 3b, 4b和 6b化合物的体内抗肿瘤活性
为了比较本发明化合物与背景技术中提到的 3b, 4b和 6b化合物的抗肿瘤活性,发 明人按照实验例 2的方法测定了先前的研究中发现的 3b, 4b和 6b化合物的体内抗肿瘤 活性。测定表明,在本发明 M1-M11, E1-E11或 C1-C11之一的化合物所用的 0.25 μηιοΐ/kg 剂量下, 3b, 4b和 6b化合物皆没有抗肿瘤作用。 在 8.9 μηιοΐ/kg的高剂量下, 3b, 4b和
6b化合物也只显示比较弱的抗肿瘤活性 (结果见表 3)。
表 3发明人先前的研究 3b, 4b和 6b化合物的体内抗肿瘤活性
n = 12。 a)与生理盐水组及阿霉素组比 p < 0.01。 本发明化合物与习知的仅由甲基连接的或脂肪烃基取代甲基连接的双吲哚乙酸衍 生物或类似物相比, 不但大大提高抗肿瘤活性, 同时显著降低神经毒性与毒副作用。
Claims
权利要求书
其中 R为氢或 d-C6烷基; Ar为未取代、 或被一个或多个相同或不同的取代基取代 的芳基, 所述取代基选自卤素、 羟基、 硝基、 d-C6烷氧基、 亚甲二氧基、 亚乙二氧 基所构成的群组。
2. 根据权利要求 1所述的化合物, 其中所述 6烷基为甲基、 或乙基。
3. 根据权利要求 1所述的化合物, 其中所述卤素为氟、 氯、 或溴。
4. 根据权利要求 1所述的化合物, 其中所述 C C6烷氧基为甲氧基、 或乙氧基。
5. 根据权利要求 1所述的化合物, 其中 Ar为被一个至三个相同或不同的取代基取代 的芳基。
6. 根据权利要求 1所述的化合物, 其中所述芳基为苯基。
7. 根据权利要求 1所述的化合物, 其中 R为氢、 甲基或乙基, 且 Ar选自对羟基苯基、 对氯苯基、 间硝基苯基、 3-甲氧基 -4-羟基苯基、 3,5-二甲氧基 -4-羟基苯基、 3,4-二羟 基苯基、 4-甲氧基苯基、 3,4-二甲氧基苯基、 3,4-亚甲二氧基苯基、 2-羟基 -4-羧基苯 基、 和 2-羟基苯基所构成的群组。
8. 一种药物组合物, 该药物组合物包含: 如权利要求 1至 7任一项所述的化合物, 及 药学上可接受的载剂。
9. 一种权利要求 1至 7任一项所述的化合物在制备抗肿瘤药物中的应用。
其中 R为氢或 CrC6烷基; Ar为未取代、 或被一个或多个相同或不同的取代基取代 的芳基, 所述取代基选自卤素、 羟基、 硝基、 d-C6烷氧基、 亚甲二氧基、 亚乙二氧 基所构成的群组;
所述制备方法包括:
在催化剂存在下的溶剂系统中縮合吲哚乙酸和具有以下通式 P的经取代醛,
0
f t P
、
Ar H 而得到所述式 I化合物;
其中当 R为氢时, 所述溶剂系统为惰性溶剂, 而当 R为 6烷基时, 所述溶剂系 统为相应的 d-c6烷醇。
11. 根据权利要求 10所述的制备方法, 其中所述卤素为氟、 氯、 或溴。
12. 根据权利要求 10所述的制备方法, 其中所述 d-C6烷氧基为甲氧基、 或乙氧基。
13. 根据权利要求 10所述的制备方法, 其中 Ar为携带一个至三个相同或不同的所述取 代基的苯基。
14. 根据权利要求 13所述的制备方法, 其中 Ar选自对羟基苯基、 对氯苯基、 间硝基苯 基、 3-甲氧基 -4-羟基苯基、 3,5-二甲氧基 -4-羟基苯基、 3,4-二羟基苯基、 4-甲氧基苯 基、 3,4-二甲氧基苯基、 3,4-亚甲二氧基苯基、 2-羟基 -4-羧基苯基、 和 2-羟基苯基所 构成的群组。
15. 根据权利要求 10所述的制备方法, 其中所述催化剂为浓硫酸或浓盐酸。
16. 根据权利要求 10所述的制备方法, 其中 R为甲基或乙基, 且所述 CrC6烷醇为甲醇 或乙醇。
17. 根据权利要求 10所述的制备方法, 其中所述惰性溶剂选自乙醚、 四氢呋喃、 乙二醇 二甲醚、 二甲基亚砜 (DMSO) 、 二甲基甲酰胺 (DMF) 构成的群组。
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