WO2014194795A1 - 吲哚酮化合物或其衍生物及其用途 - Google Patents
吲哚酮化合物或其衍生物及其用途 Download PDFInfo
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- WO2014194795A1 WO2014194795A1 PCT/CN2014/078929 CN2014078929W WO2014194795A1 WO 2014194795 A1 WO2014194795 A1 WO 2014194795A1 CN 2014078929 W CN2014078929 W CN 2014078929W WO 2014194795 A1 WO2014194795 A1 WO 2014194795A1
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- Prior art keywords
- compound
- methyl
- deuterated
- compound according
- anthrone
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- 210000003802 sputum Anatomy 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- HKSZLNNOFSGOKW-FYTWVXJKSA-N staurosporine Chemical compound C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1[C@H]1C[C@@H](NC)[C@@H](OC)[C@]4(C)O1 HKSZLNNOFSGOKW-FYTWVXJKSA-N 0.000 description 1
- CGPUWJWCVCFERF-UHFFFAOYSA-N staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(OC)O1 CGPUWJWCVCFERF-UHFFFAOYSA-N 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
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- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- QENJZWZWAWWESF-UHFFFAOYSA-N tri-methylbenzoic acid Natural products CC1=CC(C)=C(C(O)=O)C=C1C QENJZWZWAWWESF-UHFFFAOYSA-N 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
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- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- C07D403/12—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 chain containing hetero atoms as chain links
Definitions
- the present invention relates to an anthrone compound or a derivative thereof and use thereof, and belongs to the technical field of chemical medicine.
- VEGFR vascular endothelial growth factor receptor
- FGFR fibroblast growth factor receptor
- PDGFR angiogenesis inhibitors inhibit tumor formation and internal vascularization, which in turn reduces the oxygen and nutrient supply of the tumor, leading to tumor cell shrinkage and death. This anti-tumor treatment is compared with traditional chemotherapy methods. Than, there are fewer side effects.
- BIBF 1120 Nintedanib has a good effect on a variety of tumors such as liver cancer, lung cancer, rectal cancer, uterine cancer, brain cancer metastatic colorectal cancer and so on.
- Clinical phase I data indicate that BIBF 1120 monotherapy is well tolerated in the treatment of advanced malignant tumors.
- a phase II clinical double-blind trial of BIBF 1120 in patients with recurrent advanced non-small cell lung cancer showed that BIBF 1120 showed better data than other angiogenesis inhibitors in a similar patient population, as for safety, hypertension The incidence of bleeding and thromboembolism was also low, and no patients developed hand-foot syndrome.
- Niobium is obtained by distilling D 2 0 (heavy water) from a large amount of water. By HD exchange by heavy water, a compound of the desired site can be obtained. Hydrogen in 10%-15% of body fluids in mice and dogs was replaced with sputum for a long time, and no significant effect was observed, although the concentration of sputum increased to 25% and was generally toxic to these organisms. According to Wallace et al., even if the body's heavy water (D 2 0) accounts for 23% of the body fluid, no toxicity is found in the short term.
- Deuterated drugs are quite different from all-hydrogen compounds in terms of their metabolism. CD bonds are usually 6-10 times more stable than CH bonds. These stronger bonds are difficult to break and can reduce the bond breaking rate. This effect is It is called the isotope effect (KIE). This advantage can directly affect the absorption, distribution, metabolism and excretion of certain drugs. Thereby improving the safety, effectiveness and tolerability of the drug and prolonging its half-life. Moreover, the deuterated compound retains the same physicochemical properties as the parent compound (solubility, melting point, ability to bind to the receptor, etc.).
- ⁇ enriched drugs may be safer than the mother, or reduce the production of toxic metabolites
- ⁇ enriched drugs relative to the mother may reduce the single dose
- the technical problem to be solved by the present invention is to provide a new drug for the prevention or treatment of cancer in the clinic: a new class of anthrone compounds or derivatives thereof.
- R 24 and R 25 each independently represent a non-deuterated, one or more deuterated or full deuterated ⁇ . 4 ⁇ base;
- R 10 , Rn > R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , Ri9 > R 2 o R 2 i R 22 or R 23 each independently represents H or D ;
- the compound of formula (a) has at least one D.
- R 2 , R 3 , R 5 , R 7 , R 8 , R 9 and Ri are preferred.
- Ru, R 12 , Rl3 Rl4, Rl5, Rl6, Rl7, Rl8 Rl9 R 2 o R 2 i R 22 or R 23 each independently represent H, and the structural formula is as shown in the following formula (b):
- R 24 is undeuterated, one or more deuterated or fully deuterated
- R 24 is one or more times deuterated or fully deuterated ⁇ ⁇ further, based on the formula (b), preferably R 24 is once or Many times or all generations of ⁇ 3 ⁇ 4 ⁇ Based on the formula (b), it is preferred that R 24 is -CH 2 D, -CHD 2 or -CD 3 .
- R 24 is -CD 3 ; the structural formula is as shown in the following formula (c):
- an undeuterated ⁇ fluorenyl group is preferred.
- R 25 is an undeuterated, one or more deuterated or fully deuterated Ci ⁇ C 4 fluorenyl group.
- R 25 is an undeuterated ⁇ C 4 fluorenyl group.
- R 25 is preferably -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 or -(CH 2 ) 3 CH 3 .
- R 25 is preferably -CH 3 or -CH 2 CH 3 .
- the compound of the invention is:
- a second technical problem to be solved by the present invention is to provide various crystal forms of the above anthrone compounds, pharmaceutically acceptable salts thereof or solvent compounds thereof.
- a third technical problem to be solved by the present invention is to provide a drug for preventing or treating cancer, the active ingredient comprising the above-mentioned anthrone compound or various crystalline forms of the above-mentioned anthrone compound, and a pharmaceutically acceptable salt thereof Or its solvent compound.
- the invention has the beneficial effects: the anthrone compound of the invention forms a cerium-enriched compound by the hydrazine-substituted fluorenone compound Nintedanib, and the fluorenone compound of the invention has a high blood concentration,
- the blood concentration of the inventive compound B is much higher than that of Nintedanib, so that the drug acts in the body for a long time, prolongs the anticancer half-life of the indole compound, thereby prolonging the drug effect.
- Figure 1 is a plasma drug concentration-time curve after a single gavage of Ninedanib in mice
- Figure 2 is a plasma drug concentration-time curve after a single intragastric administration of Compound A
- Figure 3 is a plasma drug concentration-time curve after a single intragastric administration of Compound B
- Figure 4 is a plasma drug concentration-time curve after a single intragastric administration of Compound C in mice
- Figure 5 is a plasma drug concentration-time curve after a single intragastric administration of Ninedanib, Compounds A, B, and C;
- Figure 6 is a tumor volume growth curve of BIBF 1120, Compound B in an in vivo antitumor activity test;
- Figure 7 is a graph showing the changes in body weight of mice in the antitumor activity test of BIBF 1120 and Compound B in vivo.
- the technical problem to be solved by the present invention is to provide a new drug for the prevention or treatment of cancer in the clinic: a new class of anthrone compounds or derivatives thereof.
- the anthrone compound of the formula (a) is:
- R 24 and R 25 each independently represent a non-deuterated, one or more deuterated or full deuterated ⁇ . 4 ⁇ base;
- R 10 , Rn > R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , Ri9 > R 2 o R 2 i R 22 or R 23 each independently represents H or D ;
- the compound of formula (a) has at least one D.
- the compound of the present invention is a deuterated compound, there is at least one D in the structural formula.
- R 2 , R 3 , R 5 , R 7 , R 8 , R 9 and Ri are preferred.
- Ru, R 12 , Rl3 Rl4, Rl5, Rl6, Rl7, Rl8 Rl9 R 2 o R 2 i R 22 or R 23 each independently represent H, and the structural formula of the finally obtained compound is as shown in the following formula (b):
- R 24 is undeuterated, one or more deuterated or fully deuterated.
- R 24 is one or more deuterated or fully deuterated ⁇ fluorenyl groups.
- R 24 is one or more deuterated or fully deuterated ⁇ 3 ⁇ 4 fluorenyl groups.
- R 2 4 is -CH 2 D, -CHD 2 or -CD 3 on the basis of the formula (b).
- R 24 is -CD 3 based on the formula (b) ; the structural formula of the obtained compound is as shown in the following formula (c):
- an undeuterated ⁇ fluorenyl group is preferred.
- R 25 is an undeuterated, one or more deuterated or fully deuterated Ci ⁇ C 4 fluorenyl group.
- R 25 is an undeuterated ⁇ C 4 fluorenyl group.
- R 25 is preferably -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 or -(CH 2 ) 3 CH 3 .
- R 25 is preferably -CH 3 or -CH 2 CH 3 .
- the compound of the invention is:
- the anthrone compounds of the present invention can be made into various crystal forms.
- the anthrone compound of the present invention may be formulated into a pharmaceutically acceptable salt, and the pharmaceutically acceptable salt is suitable for use as the above-mentioned anthrone compound and an acid or a base.
- the salt of the drug, the acid addition salt includes a salt formed with a pharmaceutically acceptable anion such as a salt formed with a hydrogen halide, sulfuric acid, phosphoric acid, trifluoroacetic acid, citric acid or maleic acid.
- Base addition salts include alkali metal or alkaline earth metal salts.
- the anthrone compound of the present invention can form a lipid suspension.
- the main components of the lipid suspension include a lipid carrier, a thickener and a glidant/solubilizing agent, and the lipid carrier includes corn glyceride and diethylene glycol.
- the lipid suspension made of the anthrone compound of the present invention is prepared by a conventional method known for producing a preparation, that is, by mixing the components in a predetermined order at a predetermined temperature to obtain a homogeneous suspension.
- the above formulations may be incorporated into a pharmaceutical capsule, preferably a soft gelatin capsule comprising glycerin, hard gelatin or hydroxypropyl methylcellulose (HPMC) capsules as a plasticizer, optionally encapsulated or taped.
- the capsule pharmaceutical dosage form can be prepared by conventional methods known in the literature for producing capsules.
- the soft gelatin capsules can be prepared by conventional methods known in the literature for producing soft gelatin capsules which can be packaged in suitable glass containers, soft plastic containers, aluminum bags or double poly (poly) bags. .
- the anthrone compound of the present invention can be formulated into a solvent compound such as an aqueous solvent compound.
- the preparation method of the anthrone compound of the present invention comprises the following steps:
- the synthesis of the compound 8 comprises the following steps:
- the compound 6 was suspended in toluene, acetic anhydride was added thereto, the system was heated to 90-120 ° C, and the compound 7 was slowly added to continue the reaction.
- the volatile product was evaporated, and the concentration of the toluene was kept constant, and the system was cooled.
- the mixture was stirred and suction filtered to give a crude material, which was washed successively with a mixture of toluene, toluene and ethyl acetate, and dried to give compound 8.
- the compound 4 was dissolved in acetic acid, Pd/C was added, and the reaction was carried out under normal pressure of hydrogen. After completion of the reaction, the catalyst was removed by filtration, the solvent was evaporated, and the product was washed with a small amount of ethyl acetate.
- the mixed solution of the compound 2 and the compound 3 dissolved in DMF is added dropwise to the DMF solution of potassium t-butoxide, and the reaction is completed at 0 to 15 ° C.
- the reaction is complete by TLC, and the reaction is completed. It was poured into a mixed solution of ice water and concentrated HCl, and extracted with ethyl acetate, and then washed with saturated NaCI, and dried and purified by column chromatography to afford crude compound 4.
- the reaction liquid is poured into a mixed solution of ice water and concentrated HC1 for the purpose of reducing the risk of acid-base reaction, and the purpose of separation of the column is to separate the purified product.
- the synthesis of the compound 12 comprises the following steps:
- the synthetic route of the compound 12 is as follows:
- the progress of the reactant reaction can be detected by TLC in the above preparation method.
- the raw material deuterated compound in the above method for synthesizing an anthrone compound is partially obtained by deuteration of a raw material compound, and is partially purchased.
- oxime compound of the present invention or various crystalline forms of the oxime compound of the present invention, a pharmaceutically acceptable salt thereof, or a solvate thereof for the preparation of a medicament for treating or preventing cancer and related diseases.
- the cancer includes liver cancer, lung cancer, rectal cancer, uterine cancer, brain cancer or metastatic intestinal cancer.
- the present invention provides a medicament for preventing or treating cancer, which comprises the above-mentioned anthrone compound or various crystal forms of the above-described indolone compound, a pharmaceutically acceptable salt thereof or a solvent compound thereof.
- a method for producing a medicament for preventing or treating cancer according to the present invention which comprises one or more of an anthrone compound, various crystal forms of the above anthrone compound, a pharmaceutically acceptable salt thereof, and a solvent compound thereof It is mixed with a pharmaceutically acceptable carrier to prepare a medicament for preventing or treating cancer.
- the above-mentioned drugs for preventing or treating cancer can be formulated into various dosage forms including injections, capsules, tablets, pills, powders or granules.
- 2-nonanone-6-formic acid trimethyl ester (5-1) (4.0 g, 20.71 mmol) was suspended in 12 mL of toluene at room temperature, and chloroacetic anhydride (5.4 g, 30.95 mmol) was added to the above suspension. The mixture was heated to reflux for 3 h, cooled to 80 ° C, EtOAc (EtOAc) (EtOAc) g (yield 93.5%), the compound 1-chloroacetyl-2-indanone-6-carboxylic acid trimethyl ester (6-1).
- Methyl 2-nonanone-6-carboxylate (5-2) (4.0 g, 20.71 mmol) was suspended in 12 mL of toluene at room temperature, and chloroacetic anhydride (5.4 g, 30.95 mmol) was added to the above suspension. The mixture was heated to reflux for 3 h, cooled to 80 ° C, EtOAc (EtOAc) (EtOAc) 93.5%), the compound 1-chloroacetyl-2-indanone-6-carboxylic acid methyl ester (6-2).
- Methyl ketone-6 methyl formate (8-2) (800mg, 2mmol) in methanol 3.2mL) in the suspension, the reaction system is stirred for 30min, cooled to 0 ° C, stirring at 0 ° C for 2 h, suction filtration, methanol Washing and drying to obtain 600 mg (94.6%) of a yellow solid, compound (E)-methyl-3-(methoxy(phenyl)methylene)-2-indanone-6-carboxylic acid methyl ester (9-2 ).
- Piperazine (1.0 g, 11.6 mmol) and piperazine hydrochloride (1.845, 11.6 mmol) were dissolved in ethanol / deuterated water (5:1), refluxed for 1 hour and cooled to 0 °C.
- Deuterated iodothymidine (0.85 mL, 9.29 mmol) was added dropwise, and then stirred at ambient temperature for 90 min. After the temperature of the system was lowered to 0 ° C, the pH was adjusted to about 9.0 with a 2 mol/L aqueous sodium hydroxide solution. Extraction, distillation, and collection of 120-130 product gave 0.7 g (yield 58.3%) as a colorless liquid.
- Example 2 According to the method described in Example 1, the difference is that: 4-methylpiperazine is replaced with 4-trimethylpiperazine to prepare the target compound, wherein 4--3-mercaptomethylpiperazine is synthesized. As described in Example 2.
- Example 1 The CD 3 OD in Example 1 was replaced with CD 2 HOH according to the method described in Example 1, and the trimethyl chloroacetate in Example 1 was replaced with methyl chloroacetate.
- dimethyl chloroacetate is as follows: 5 g of chloroacetyl chloride is dissolved in 20 mL of dry dichloromethane, and at 0 V, 1.76 g of CD 2 HOH is slowly added to the system, and stirred for 1 hour. This was washed with water, a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered, and evaporated.
- the difference is: using d 4 -m-nitrobenzoic acid instead of m-nitrobenzoic acid, replacing d4-methanol, methyl chloroacetate to replace trimethyl chloroacetate, thereby obtaining Target compound.
- the difference is: replacing N-methylpiperazine with N-methyl-2,3,5,6-octapiperazine, replacing d4-methanol with methanol, methyl chloroacetate
- N-methyl-2,3,5,6-octapiperazine is commercially available.
- Example 8 Compound H: (Z)-3-((4-(N-methyl-2-(4-methylpiperazin-1-substituted)acetamido)anilinyl) (2, Preparation of methyl 3, 4, 5, 6-pentaphenyl)methylene)-2-indanone-6-carboxylate
- the difference is: replacing the d 4 -methanol with the original trimethyl benzoic acid trimethyl ester instead of the original benzoic acid trimethyl hydrazine, and the methyl chloroacetate replacing the trimethyl chloroacetate
- the target compound was obtained.
- the difference is that N-trimethylmethyl-p-nitroaniline is substituted for N-methyl-p-nitroaniline, methanol is substituted for d4-methanol, and methyl chloroacetate is substituted for trichlorohydrin. Methyl ester to thereby obtain the target compound.
- N-trimethylmethyl-p-nitroaniline The synthetic route of N-trimethylmethyl-p-nitroaniline is referred to Ullmann amination reference Jiao Jiao. J. Org. Chem. 2011, 76, 1180-1183. N-trimethyl-p-nitroaniline HRMS: 155.0776.
- Example 11 Compound K : (Z) 7-Indol-3- ((4-(N-methyl-2-(4-trimethylsulfazine)-1-substituted)acetylamino)anilinyl) (phenyl Preparation of methyl methylene)-2-indanone-6-carboxylate
- Example 2 Following the procedure of Example 1, wherein the compound 2- ⁇ -3 nitrobenzoic acid was used in place of the compound nitrobenzoic acid, methanol was substituted for d4-methanol, and methyl chloroacetate was substituted for trimethyl chloroacetate.
- Example 12 Compound L: (Z) -3- ((4-(N-methyl-2-(4-methyl-2,6-tetrapiperazin-1-substituted) acetylamino) anilino) ( Preparation of Phenyl)methylene)-2-indanone-6-carboxylic acid methyl ester
- the inventors of the present invention screened three compounds FGFR-1, KDR, PDGFR-a in vitro, each compound was started from lOuM, diluted 3 times, and tested at 10 concentration points (2 complex wells). The compound staurosporine was used as a standard control.
- Km ATP represents the ATP concentration corresponding to the maximum reaction rate of the kinase with ATP.
- PDGFRa from Invitrogen, Cat. No. PR7346A, Lot. No. 682476L
- EDTA from Sigma, Cat. No. E5134, CAS No. 60-00-4.
- 96-well plate from Corning, Cat. No. 3365, Lot. No. 22008026)
- mM/L refers to the concentration of material per liter of target fluid.
- 100 mM/L HEPES in the stop solution refers to a concentration of 100 mmol/L HEPES in the 1 L stop solution.
- test compounds were dissolved in 100% DMSO to a concentration of 10 mM.
- concentration of the compound was determined to be 10 ⁇ .
- the unit of IC 5Q in Table 1 is nM/L.
- mice were intragastrically administered with Nintedanib, Compound A, Compound B and Compound C.
- Whole blood samples were collected at different time points, and plasma was separated.
- the total drug concentration in plasma was determined by liquid chromatography-tandem mass spectrometry.
- Healthy Balb/c mice male, weighing 18 to 20 g. 50 mg/mL of Nintedanib, Compound A, Compound B, and Compound C were respectively administered by single gavage, and the compound was dissolved in a 0.5% (w/v) hydroxypropylmethylcellulose solution at a volume of 10 mL/kg. Fasting for 12 hours before administration, free drinking water. After 6 hours of administration, they were fed uniformly.
- 0.5, 1.0, 2.0, 4.0, 6.0 and 24.0 h 3 mice at each time point, 0.3 mL of blood was taken from the posterior venous plexus of the mouse, placed in heparinized tubes, centrifuged at 3500 rpm for 10 min, and plasma was separated. Store in a freezer at -80 °C.
- mice were given a single intragastric administration of a concentration of 50 mg/mL, and a dose of 10 mL/kg of Nintedanib, Compound A, Compound B, and Compound C.
- the blood concentration-time curve of the mouse is shown in Figure 1, Figure 2, Figure 3, and Figure. 4, Figure 5.
- mice The pharmacokinetic parameters of the mice after a single intragastric administration of a concentration of 50 mg/mL and a dose of 10 mL/kg of Nintedanib, Compound A, Compound B, and Compound C are shown in Table 2.
- Table 2 The pharmacokinetic parameters of the mice after a single intragastric administration of a concentration of 50 mg/mL and a dose of 10 mL/kg of Nintedanib, Compound A, Compound B, and Compound C are shown in Table 2.
- Table 2 The pharmacokinetic parameters of the mice after a single intragastric administration of a concentration of 50 mg/mL and a dose of 10 mL/kg of Nintedanib, Compound A, Compound B, and Compound C are shown in Table 2.
- Compound B has a higher blood concentration in mice than Nintedanib, Compound A, and Compound C.
- the in vivo plasma concentration of Compound C is slightly lower than that of Nintedanib, and the blood concentration of Compound A is significantly lower than that of Nintedanib.
- the compound A obtained by deuteration of the methoxy group of Nintedanib ⁇ ring has significantly lower pharmacokinetic parameters in mice than Nintedanib, because the methoxy deuteration reduces the absorption of the drug in mice.
- the compound B obtained by deuteration of the nitrogen methyl group of the piperazine ring of Nintedanib was significantly better than Nintedanib in mice because the deuteration of the nitrogen methyl group on the piperazine ring weakened or blocked the corresponding metabolic enzyme.
- the metabolism of compound B is higher than that of Nintedanib, and the residence time in the body is prolonged.
- the overall pharmacokinetic parameters are better than Nintedanib; the deuteration of the sulfhydryl group on the piperazine ring will weaken or block the corresponding The metabolism of a compound by a metabolic enzyme, thereby prolonging the residence time of the compound in the body.
- FaDu was cultured in RPMI 1640+10% FBS medium; when the cell confluence in the logarithmic growth phase reached 80%-90%, trypsinization, centrifugation, and washing the cells three times with double-free medium, and then counting Finally, the cells were resuspended in medium without double.
- the mice were randomly divided into groups of 7 cells, respectively, solvent control group, compound B (50 mg/kg), and compound B (25 mg/kg). ), Compound B (12.5 mg/kg), compound BIBF 1120 (25 mg/kg).
- the drug was administered orally by intragastric administration at a frequency of once a day for 27 days, and tumor volume measurement was performed every three days.
- the tumor volume growth curve was obtained as shown in Fig. 6.
- the inhibition rate of compound B at a concentration of 50 mg/kg was 97.4%; the inhibition rate at a concentration of 25 mg/kg was 87.9%; and the concentration was 12.5 mg/
- the inhibition rate was 63.0% at kg and 82.3% at 25 mg/kg for BIBF 1120. It showed that the compound B was slightly better than the positive control compound BIBF 1120 when the concentration was 25 mg/kg; when the concentration was 50 mg/kg, the tumor was basically inhibited from growing.
- the mouse body weight change curve is shown in Figure 7.
- the weight change curve of the mouse in Figure 7 showed that the weight loss of Compound B in the three different dose groups was larger than that of the positive control group, indicating that the toxicity of Compound B was greater than that of the positive control compound BIBF 1120.
- the vehicle is specifically a solvent control group, that is, 0.5% hydroxyethyl cellulose is given.
- the FaDu cell line was purchased from the American Type culture collection (ATCC); the compound B and BIBF 1120 were synthesized by the State Key Laboratory of Biotherapy of Sichuan University; the RPMI-1640 medium was purchased from Thermo Fisher Scientific; FBS Fetal bovine serum was purchased from Gibco; trypsin was purchased from Invitrogen; streptomycin was purchased from Dalian Bao Biotech Co., Ltd.; Solvent hydroxyethylcellulose (4,500-6,500 mPa. S ) for formulating drugs; TCI required; Grade BALB/c nude mice were purchased from Beijing Huakangkang Biotechnology Co., Ltd., 5 6 weeks old, weighing 18 20g, all female.
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Abstract
本发明涉及通式(a)所示的吲哚酮化合物或其衍生物及其用途。本发明所解决的技术问题是提供了吲哚酮化合物或其衍生物及其用途。本发明采用氘取代吲哚酮化合物得到的一类氘富集的吲哚酮化合物,上述吲哚酮化合物,可同时作用于血管生成过程中涉及的3种关键受体家族-血管内皮生长因子受体(VEGFR)、成纤维细胞生长因子受体(FGFR)以及血小板衍生生长因子受体(PDGFR),抑制血管生成,从而达到治疗癌症的效果,上述氘代吲哚酮化合物或其衍生物作为药物具有高效的优点。
Description
吲哚酮化合物或其衍生物及其用途 技术领域
本发明涉及吲哚酮化合物或其衍生物及其用途, 属于化学医药技术领域。
背景技术
Nintedanib (BIBF 1120), 其结构式如下:
是一种新型口服有效的血管抑制剂, 可同时作用于血管生成过程中涉及的 3中关键受体 家族一血管内皮生长因子受体 (VEGFR)、 成纤维细胞生长因子受体 (FGFR) 以及血小板衍 生生长因子受体 (PDGFR 血管生成抑制剂抑制肿瘤周围以及内部血管形成, 继而降低了 肿瘤的氧气和营养供给, 从而导致肿瘤细胞缩小、 死亡。 这种抗肿瘤的治疗方法与传统的化 疗方法相比, 有较少的副作用。
Nintedanib (BIBF 1120) 对多种肿瘤如肝癌、 肺癌、 直肠癌、 子宫癌、 脑癌转移性肠癌 等等有较好疗效。 临床一期数据表明: BIBF 1120单一疗法在晚期的恶性肿瘤耐的治疗中耐 受性良好。 BIBF 1120对于治疗复发性晚期非小细胞肺癌患者的 II期临床双盲实验表明, 在 类似的患者群体中, BIBF 1120 相比其他血管生成抑制剂表现出较好的数据, 至于安全方面, 高血压、 出血和血栓栓塞的发生率也较低, 没有病人出现手脚综合症。
氘是通过从大量水多次蒸馏得到 D20 (重水) 而来的。 通过重水发生 H-D交换, 可以得 到期望位点氘代的化合物。 老鼠和狗的 10%-15%体液的氢用氘长期代替, 未发现明显影响, 尽管当氘的浓度升高至 25%普遍对这些生物有毒。 根据 Wallace等研究, 即使人体内重水 (D20) 占体液的浓度高达 23%时, 在短期内未发现毒性。
氘代药物由于其代谢方面与全氢化合物存在相当大的区别, C-D键通常情况下比 C-H键 稳定 6-10倍, 这些更强的键很难断裂, 可以降低键的断裂速率, 这个效应被称作同位素效应 (KIE)。 这一优点可直接影响某些药物的吸收、 分布、 代谢和排泄等属性。 从而提高药物的 安全性、 有效性和耐受性, 延长其半衰期。 而且氘代化合物保持了与母体化合物相同的物理 化学性质 (溶解性、 熔点和与受体结合的能力等)。
氘富集化合物或药物相对于母体化合物有下面几个特点:
1 ) 缩短药物研发周期, 减少药物研发成本和降低研发风险;
2) 氘富集药物相对于母体可能更安全, 或减少有毒代谢物的生成;
3 ) 氘富集药物相对于母体作用更长时间或更好的疗效;
4) 氘富集药物相对于母体, 可能降低单次给药剂量;
5 ) 有可能减少不同患者之间对药物的不同反应。
虽然氘代化合物具有上述优点, 但是, 并非所有的氘代化合物都有比原本化合物更好的 效果, 氘代位置的不同直接影响药物的疗效和药物的半衰期。 目前为止, 未见吲哚酮化合物 Nintedanib氘代的报道。
发明内容
本发明所要解决的技术问题是为临床提供一种新的预防或治疗癌症药物: 一类新的吲哚 酮化合物或其衍生物。
本发明的技术方案: 通式 (a) 所示吲哚酮化合物
R2、 R3、 R4、 R5、 R^、 R7、 R8、 !¾、 R10、 Rn > R12、 R13、 R14、 R15、 R16、 R17、 R18、 Ri9 > R2o R2i R22或 R23每一个独立表示 H或 D ;
式 (a) 所示化合物至少有一个 D。
进一步地, 在通式 (a) 的基础上, 优选 R2、 R3、 、 R5、 、 R7、 R8、 R9、 Ri。、 Ru、 R12、 Rl3 Rl4、 Rl5、 Rl6、 Rl7、 Rl8 Rl9 R2o R2i R22或 R23每一个独立表示 H, 其结构式 如下通式 (b ) 所示:
Ci ~C4焼基。
进一步地, 在通式 (b ) 的基础上, 优选 R24为一次或多次氘代的或全氘代的 〜 垸 进一步地, 在通式 (b ) 的基础上, 优选 R24为一次或多次氘代的或全氘代的 〜¾垸
在通式 (b) 的基础上, 优选 R24为 -CH2D、 -CHD2或 -CD3。
在通式 (b) 的基础上, 优选 R24为 -CD3 ; 其结构式如下通式 (c) 所示:
(c)。
进一步地, 在通式 (c) 的基础上, 优选 为未氘代的、 一次或多次氘代的或全氘代的 Ci~C4焼基。
进一步地, 在通式 (c) 的基础上, 优选 为未氘代的 〜 垸基。
进一步地, 在通式 (c) 的基础上, 优选 为 ¾、 -CH2CH3、 - (CH2) 2CH3或- (CH2) 3CH3。
进一步地, 在通式 (c) 的基础上, 优选 为-。¾或 -CH2CH3。
进一步地, 在通式 (c) 的基础上, 优选 为 ¾; 其结构式如下通式 (d) 所示:
(d)。
进一步地, 在通式 (d) 的基础上, 优选 R25为未氘代的、 一次或多次氘代的或全氘代的 Ci~C4焼基。
进一步地, 在通式 (d) 的基础上, 优选 R25为未氘代的 〜C4垸基。
进一步地, 在通式 (d) 的基础上, 优选 R25为 -CH3、 -CH2CH3、 - (CH2) 2CH3或- (CH2) 3CH3。
进一步地, 在通式 (d) 的基础上, 优选 R25为 -CH3或 -CH2CH3。
本发明所要解决的第二个技术问题是提供了上述吲哚酮化合物的各种晶型、 其药学上可 接受的盐或其溶剂化合物。
本发明所要解决的第三个技术问题是提供了一类预防或治疗癌症的药物, 其活性成分包 含上述吲哚酮化合物或上述吲哚酮化合物的各种晶型、其药学上可接受的盐或其溶剂化合物。
本发明具有的有益效果: 本发明所述的吲哚酮化合物, 通过氘取代吲哚酮化合物 Nintedanib 形成了氘富集化合物, 本发明所述的吲哚酮化合物具有较高的血药浓度, 本发明 化合物 B的血药浓度远高于 Nintedanib, 使药物在体内作用时间长, 延长了吲哚酮化合物的 抗癌半衰期, 从而延长药效。
附图说明
图 1是小鼠单次灌胃给予 Ninedanib后的血浆药物浓度 -时间曲线;
图 2是小鼠单次灌胃给予化合物 A后的血浆药物浓度 -时间曲线;
图 3是小鼠单次灌胃给予化合物 B后的血浆药物浓度 -时间曲线;
图 4是小鼠单次灌胃给予化合物 C后的血浆药物浓度 -时间曲线;
图 5是小鼠单次灌胃给予 Ninedanib、 化合物 A、 B和 C后的血浆药物浓度 -时间曲线; 图 6是 BIBF 1120、 化合物 B在体内抗肿瘤活性实验中肿瘤体积生长曲线;
图 7是 BIBF 1120、 化合物 B在体内抗肿瘤活性实验中小鼠体重变化曲线。
具体实施方式
本发明所要解决的技术问题是为临床提供一种新的预防或治疗癌症药物: 一类新的吲哚 酮化合物或其衍生物。
本发明的技术方案: 通式 (a) 所示吲哚酮化合物为:
( a)
其中, 、 R24、 R25每一个独立表示未氘代的、 一次或多次氘代的或全氘代的 〜。4垸 基;
R2、 R3、 R4、 R5、 R^、 R7、 R8、 !¾、 R10、 Rn > R12、 R13、 R14、 R15、 R16、 R17、 R18、 Ri9 > R2o R2i R22或 R23每一个独立表示 H或 D ;
式 (a) 所示化合物至少有一个 D。
由于本发明化合物是氘代化合物, 所以结构式中至少有一个 D。
进一步地, 在通式 (a) 的基础上, 优选 R2、 R3、 、 R5、 、 R7、 R8、 R9、 Ri。、 Ru、 R12、 Rl3 Rl4、 Rl5、 Rl6、 Rl7、 Rl8 Rl9 R2o R2i R22或 R23每一个独立表示 H, 最终得到 化合物的结构式如下通式 (b) 所示:
(b)。
进一步地, 在通式 (b) 的基础上 优选 R24为未氘代的、 一次或多次氘代的或全氘代的
Ci ~C4焼基。
进一步地, 在通式 (b) 的基础上 优选 R24为一次或多次氘代的或全氘代的 〜 垸 基。
进一步地, 在通式 (b) 的基础上 优选 R24为一次或多次氘代的或全氘代的 〜¾垸 基。
进一步地, 在通式 (b) 的基础上 优选 R24为 -CH2D、 -CHD2或 -CD3。
进一步地, 在通式 (b ) 的基础上 优选 R24为 -CD3 ; 得到化合物的结构式如下通式 (c ) 所示:
(c)。
进一步地, 在通式 (c) 的基础上, 优选 为未氘代的、 一次或多次氘代的或全氘代的 Ci~C4焼基。
进一步地, 在通式 (C ) 的基础上, 优选 为未氘代的 〜 垸基。
进一步地, 在通式 (c) 的基础上, 优选 为 ¾、 -CH2CH3、 - (CH2) 2CH3或- (CH2) 3CH3。
进一步地, 在通式 (c) 的基础上, 优选 为-。¾或 -CH2CH3。
进一步地, 在通式 (c) 的基础上, 优选 为 ¾; 得到化合物的结构式如下通式 (d) 所示:
(d)。
进一步地, 在通式 (d) 的基础上, 优选 R25为未氘代的、 一次或多次氘代的或全氘代的 Ci~C4焼基。
进一步地, 在通式 (d) 的基础上, 优选 R25为未氘代的 〜C4垸基。
进一步地, 在通式 (d) 的基础上, 优选 R25为 -CH3、 -CH2CH3、 - (CH2) 2CH3或- (CH2) 3CH3。
进一步地, 在通式 (d) 的基础上, 优选 R25为 -CH3或 -CH2CH3。
本发明所述吲哚酮化合物可以制成各种晶型。
为了更便于临床应用, 本发明所述的吲哚酮化合物可以制成药学上可接受的盐, 所述的 药学上可接受的盐是上述吲哚酮化合物与酸或碱所形成的适合用作药物的盐, 酸加成盐包括与 提供医药上可接受的阴离子所形成的盐, 如与卤化氢、 硫酸、 磷酸、 三氟乙酸、 柠檬酸或马 来酸形成的盐。 碱加成盐包括碱金属盐或碱土金属盐。
本发明吲哚酮化合物可以形成脂质悬浮液, 脂质悬浮液的主要成分包括脂质载体、 增稠 剂及助流剂 /增溶剂, 脂质载体包括玉米油甘油酯、 二乙二醇单乙基醚、 乙醇、 甘油、 聚乙二 醇四氢呋喃甲基醚(glycoforol)、 聚乙二醇甘油 (macrogolycerol)、 辛基癸酸酯、 聚乙二醇甘 油亚油酸酯、 中链部分甘油酯, 中链甘油三酯、 聚乙二醇 300、 聚乙二醇 400、 聚乙二醇 600、 聚氧蓖麻油、 聚氧氢化蓖麻油、 丙二醇单辛酸酯、 丙二醇单月桂酸酯、 精制豆油、 三醋酸甘 油酯和柠檬酸三乙酯中至少一种; 该增稠剂系包括形成油凝胶的赋形剂, 如胶体硅石或膨润 土、 高粘度之亲酯性或两亲性赋形剂, 如聚氧氢化蓖麻油、 氢化植物油聚乙二醇甘油-羟基硬 脂酸酯、聚乙二醇甘油-蓖麻油酸酯或硬脂肪; 助流剂 /增溶剂系选自卵磷脂, 一种或多种聚乙 二醇甘油类、 聚乙二醇甘油 -羟基硬脂酸酯或聚乙二醇甘油-蓖麻油酸酯。
本发明所述吲哚酮化合物制成的脂质悬浮液采用已知生产制剂的常规方法制备, 即藉由 在预定温度, 依预定顺序混合该等成分, 获得均质悬浮液。
上述的制剂可加入医药胶囊内, 优选软质明胶胶囊, 该胶囊壳包括作为增塑剂的甘油、 硬明胶或羟丙基甲基纤维素 (HPMC) 胶囊, 视情况可密封或带状包装。 该胶囊医药剂型可 藉由文献中已知生产胶囊之常规方法制备。 该软质明胶胶囊可藉由文献中已知生产软质明胶 胶囊之常规方法制备, 所述的胶囊可包装于适宜的玻璃容器、 柔软塑料容器、 铝袋或双层聚 乙烯 (poly) 袋中。
本发明所述吲哚酮化合物可制成溶剂化合物, 如水溶剂化合物。
本发明所述吲哚酮化合物的制备方法, 包括如下步骤:
15 ( a) 将化合物 9和化合物 15的氘代甲醇悬浮液加热回流 6 10h, 冷却, 持续搅拌, 抽滤, 甲醇洗涤, 干燥得产品, 即通式 (a) 所示结构的化合物。
进一步地, 优选所述化合物 9的合成路线如下所示:
将溶有 KOH的 CH3OH溶液加入到化合物 8 的氘代甲醇悬浮液中, 反应体系继续搅拌
15' -45min, 冷却, 继续搅拌 l〜3h, 抽滤, 甲醇洗涤, 干燥得到化合物 9。
进一步地, 优选所述化合物 8的合成包括如下步骤:
所述化合物 8
取化合物 6悬浮于甲苯中, 向其中加入乙酸酐, 对体系加热到 90〜120°C, 慢慢加入化 合物 7, 继续反应, 待易挥发产物挥发出去, 加入甲苯保持体系浓度不变, 体系冷却, 搅拌, 抽滤得到粗品, 依次用甲苯、 甲苯与乙酸乙酯的混合液洗, 干燥得到化合物 8。
5 6
将氯乙酸酐加入到化合物 5 的甲苯悬浮液中, 回流加热 2〜5h, 冷却, 然后加入甲基环 己垸, 搅拌冷却至室温, 固液分离得到粗品, 用冷的 CH3OH洗涤, 干燥得白色固体即化合 物 6。
进一步地, 优选所述化合物 5的合成路线如下所示:
进一步地,
将溶于 DMF的化合物 2和化合物 3的混合溶液滴加到叔丁醇钾的 DMF溶液中, 滴加完 毕, 在 0〜- 15°C反应, TLC检测反应是否完全, 反应完毕, 将反应液倒入冰水与浓 HC1的混 合溶液中, 用乙酸乙酯萃取, 然后用饱和 NaCl洗涤, 干燥, 柱层析分离, 得到粗品化合物 4。
其中, 将反应液倒入冰水与浓 HC1的混合溶液中的目的在于降低酸碱反应的危险, 柱层 析分离的目的是分离纯化产物。
进一步地, 优选所述 2的合成路线如下所示:
1 2
将化合物 1加入氘代甲醇或甲醇中, 加入浓硫酸, 于 80〜110°C微波反应, 反应完毕, 加入二氯甲垸, 依次用饱和 NaHC03和饱和 NaCl洗涤, 无水 Na2S04干燥, 抽滤, 旋干, 得 到化合物 2。
其中, 二氯甲垸的作用是稀释、 萃取。
进一步地, 优选所述化合物 15的合成路线如下所示:
12 将化合物 12溶于甲苯中, 加热至 30〜50°C, 向其中滴加化合物 13, 加热搅拌 l〜4h, 降温, 水洗, 用异丙醇稀释甲苯的溶液体系, 加入 Pd/C, 通入 ¾, 搅拌, 过滤除去催化剂, 旋出溶剂, 残留物用乙酸乙酯 /石油醚重结晶, 用石油醚洗涤, 干燥, 得到化合物 15。
其中, 用异丙醇稀释甲苯的溶液体系的目的在于助溶。
进一步地, 优选所述化合物 12的合成包括如下步骤:
所述化合物 12的合成路线如下所示:
10 11 12 将化合物 10加入乙酸乙酯中, 加热至 50〜70, 向其中加入化合物 11和乙酸乙酯溶液, 回流, 降温至 60〜80°C, 然后加入环己垸, 结晶, 冷却, 搅拌, 过滤, 用环己垸洗, 干燥, 化合物 12。
上述制备方法中可以采用 TLC检测反应物反应的进程。
上述合成吲哚酮化合物的方法中的原料氘代化合物, 部分为由原料化合物经氘代制得, 部分购买所得。
本发明所述吲哚酮化合物或本发明所述吲哚酮化合物的各种晶型、 其药学上可接受的盐 或其溶剂化合物在制备治疗或预防癌症以及相关的疾病药物中的应用。
所述的癌症包括肝癌、 肺癌、 直肠癌、 子宫癌、 脑癌或转移性肠癌。
本发明提供了一类预防或治疗癌症的药物, 其活性成分包含上述吲哚酮化合物或上述吲 哚酮化合物的各种晶型、 其药学上可接受的盐或其溶剂化合物。
本发明预防或治疗癌症的药物的制备方法, 将所述的吲哚酮化合物、 上述吲哚酮化合物 的各种晶型、 其药学上可接受的盐和其溶剂化合物中的一种或多种和药学上可接受的载体进 行混合, 制成预防或治疗癌症药物。
上述的预防或治疗癌症的药物可制成各种剂型, 包括注射剂、 囊剂、 片剂、 丸剂、 散剂 或颗粒剂。
通过以下具体实施例, 可以进一步了解本发明, 但以下实施例并不是对发明的限定, 而
是由本发明的权利要求书和说明书限定。
实施例 1 化合物 A: (Z) -3- ( (4- (N-甲基 -2- (4-甲基哌嗪 -1-取代) 乙酰氨基)苯胺基) (苯基)亚甲基) -2-吲哚酮 -6-甲酸三氘甲酯的制备
化合物 9-1的合成路线如下所示:
化合物 2-1: 间硝基苯甲酸三氘甲酯的制备
2.0g间硝基苯甲酸( 1-1 )加入到 10mLCD3OD中,其中, CD3OD市售的,加入 80mg 98wt% 的浓硫酸, 于 100°C微波反应 10分钟, 加入 100 mL CH2C12萃取, 依次用饱和 NaHC03和饱 和食盐水洗涤,无水 Na2S04干燥,抽滤,旋干,得到产品化合物间硝基苯甲酸三氘甲酯(2-1 ) 1.95g, 收率为 88.5%。
1HNMR (CDCl3,400MHz) ; 8.86 (s,lH); 8.40 (m,2H); 7.68 (t,lH); HRMS: 184.0560 ο 化合物 4-1: 4- (2-三氘甲氧基 -2-乙酰基) -3-苯甲酸三氘甲酯的制备
3.93g叔丁醇钾 (35mmol) 溶于 30mL DMF中, 冷却到 -10°C, 将溶于 5mL DMF的间硝 基苯甲酸三氘甲酯 (2-1 ) (2.72g, 15mmol)和氯乙酸三氘甲酯 (3-1 ) ( 1.84g, 16.5mmol) 的 混合溶液滴加到上述溶液中, 滴加完后, 在 -10°C条件下反应至 TLC检测不到原料, 反应液 倒入冰水 (50mL) 与浓盐酸 (17mL) 的混合溶液中, 用乙酸乙酯萃取, 饱和食盐水洗, 干 燥, 旋干, 柱层析分离, 得到化合物 4- (2-三氘甲氧基 -2-乙酰基) -3-苯甲酸三氘甲酯 (4-1 ) 粗品 2.36g。
化合物 5-1: 2-吲哚酮 -6-甲酸三氘甲酯的制备
将 4- (2-三氘甲氧基 -2-乙酰基) -3-苯甲酸三氘甲酯(4-1 ) ( 1.982g, 7.65mmol)溶于 40mL 乙酸中, 加入 250mg 10%的 Pd/C, 10%是指 Pd在碳中的含量; 在常压氢气压力下 40°C反应 过夜。 过滤除去催化剂, 蒸去溶剂, 用少量乙酸乙酯洗涤产品, 过滤, 得到 0.61g (产率为 41%) 产品化合物 2-吲哚酮 -6-甲酸三氘甲酯 (5-1 )。
1H NMR (CDCl3,400 MHz); 3.56 (s,2H); 7.33 (s,lH)重叠到 7.34 (d,lH); 7.57 (d,lH); 10.53 (s,lH); HRMS:194.0766。
化合物 6-1: 1-氯乙酰基 -2-吲哚酮 -6-甲酸三氘甲酯的制备
室温下, 2-吲哚酮 -6-甲酸三氘甲酯 (5-1 ) (4.0g, 20.71mmol) 悬浮于 12mL的甲苯中, 将氯乙酸酐 (5.4g, 30.95mmol) 加入到上述悬浮液中, 加热回流 3h, 冷却到 80°C, 30min 加入甲基环己垸(6mL), 悬浮液搅拌冷却到室温, 抽滤得到粗品, 用冷的甲醇(4mL)洗涤, 干燥得白色固体 5.155g (产率为 93.5% ), 即化合物 1-氯乙酰基 -2-吲哚酮 -6-甲酸三氘甲酯 (6-1 )。
1H NMR (DMSO-d6,400MHz); 8.66 (s,lH); 7.86 (d,lH) ; 7.52 (d,lH) ; 4.98 (s,2H); 3.88 (s,2H); .HRMS: 270.0488。
化合物 8-1: (E)小氯乙酰基 -3- (甲氧基(苯基)亚甲基) -2-吲哚酮 -6甲酸三氘甲酯的制备 环境温度下, 1-氯乙酰基 -2-吲哚酮 -6-甲酸三氘甲酯 (6-1 ) ( 1.2g, 4.5mmol) 悬浮于甲苯
(6mL) 中, 向其中加入乙酸酐 (1.62g, 15.7mmol), 体系加热到 110°C, lh 内加入原苯甲 酸三甲酯 (7-1 ) (2.0g, 10.8mmol) ,继续反应 3h, 易挥发产物挥发出去, 加入甲苯 (4mL) 保持体系浓度不变, 体系冷却到 5°C, 搅拌 lh, 抽滤得到粗品, 依次用甲苯、 甲苯与乙酸乙 酯 (1 : 1 ) 的混合液洗, 干燥得到 1.63g 淡黄色固体即化合物 (E) -1-氯乙酰基 -3- (甲氧基 (苯基) 亚甲基) -2-吲哚酮 -6甲酸三氘甲酯 (8-1 )。
1H NMR (DMSO-de, 400 MHz); 8.73 (d,lH); 8.09 (d,lH); 7.90 (dd,lH); 7.61-7.48 (m,5H); 4.85 (s,2H); 3.78 (s,3H); HRMS:388.0915。
化合物 9-1: (E) -甲基 -3- (甲氧基(苯基) 亚甲基) -2-吲哚酮 -6-甲酸三氘甲酯的制备
溶有 KOH (41mg, 0.6mmol) 的甲醇 (0.4mL) 溶液加入到 63°C的 (E) -1-氯乙酰基 -3- (甲氧基 (苯基) 亚甲基) -2-吲哚酮 -6-甲酸三氘甲酯 (8-1 ) ( 800mg,2mmol) 的氘代甲醇 -d4 (3.2mL) 悬浮液中, 反应体系继续搅拌 30min, 冷却到 0°C, 0°C下继续搅拌 2h, 抽滤, 甲 醇洗涤, 干燥得到 600mg (产率为 94.6%) 黄色固体即化合物 (E) -甲基 -3- (甲氧基(苯基) 亚甲基) -2-吲哚酮 -6-甲酸三氘甲酯 (9-1 )。
1H NMR (CDC13, 400 MHz); 8.08 (s,lH); 7.88 (d,lH); 7.75 (m,lH); 7.52-7.56 (m,3H); 7.40-7.45 (m,3H); 3.74 (s,3H); HRMS:312.1181。
化合物 15-1的合成路线如下所示:
将 N-甲基 -4-硝基苯胺(10-1 ) (2.5g, 16.43mmol)加入乙酸乙酯 (3mL)中,加热到 60°C, 15分钟内加入氯乙酸酐 (11-1 ) (3.25g, 19mmol) 乙酸乙酯 ( 8mL) 溶液, 回流 lh, 降温到 75°C, 然后加入 10mL环己垸, 60°C结出晶体, 冷却到 0°C, 搅拌 lh, 过滤, 用环己垸洗涤, 干燥,得到白色晶体 3.2g (产率为 85.2%)即化合物 2-氯 -N-甲基 -N-(4-硝基苯基)乙酰胺(12-1 )。
XH NMR (DMSO-d6,400MHz); 8.29 (d,2H); 7.69 (d,2H); 4.35 (s,2H); 3.33 (s,3H); HRMS: 228.0322 c
化合物 15-1: N- (4-氨基苯基) -N-甲基 -2- (4-甲基哌嗪 -1-取代) 乙酰胺的制备
2g 2-氯 -N-甲基 -N- (4-硝基苯基) 乙酰胺 (12-1 ) 溶于 15mL甲苯中, 加热到 40°C, 在 30min内滴加 N-甲基哌嗪 (13-1 ) (2.19g, 2.5eq), 加热搅拌 2h, 此时控制温度为 55°C, 搅 拌完毕, 降到室温, 加入 5mL水洗, 用 15mL异丙醇稀释甲苯的溶液体系, 加入 100mg Pd/C ( 10%), 通入氢气 (4bar), 常温搅拌 3h, 过滤除去催化剂, 旋出溶剂, 残留物用乙酸乙酯 / 石油醚重结晶, 用石油醚洗涤, 干燥, 得到白色晶体 2.02g (产率为 88.0%) 即化合物 N- (4- 氨基苯基) -N-甲基 -2- (4-甲基哌嗪 -1-取代) 乙酰胺 ( 15-1 )。
1H NMR (DMSO-de, 400 MHz); 6.90 (d,2H); 6.65 (d,2H), 5.22 (2H); 3.04 (s,3H); 2.79 (s,2H); 2.32 (m,4H); 2.23 (m,4H); 2.10 (s,3H); HRMS :262.1774。
化合物 A的合成路线如下所示:
15-1 9-1
化合物 A: (Z) -3- ((4- (N-甲基 -2- (4-甲基哌嗪 -1-取代) 乙酰氨基) 苯胺基) (苯基)亚甲 基) -2-吲哚酮 -6-甲酸三氘甲酯的制备
(E) -甲基 -3- (甲氧基(苯基)亚甲基)-2-吲哚酮 -6-甲酸三氘甲酯(9-l ) (200mg,0.64mmol) 和 N- (4-氨基苯基) -N-甲基 -2- (4-甲基哌嗪 -1-取代) 乙酰胺 ( 15-1 ) ( 171mg,0.65mmol) 的 氘代甲醇 -d4 ( 1.8mL)悬浮液加热回流 8h, 缓慢冷却到 10°C, 10°C下继续搅拌 lh, 抽滤, 冷 甲醇洗, 干燥得 310mg ( 89%) 黄色固体即化合物 (Z) -3- ( (4- (N-甲基 -2- (4-甲基哌嗪 -1- 取代) 乙酰氨基) 苯胺基) (苯基) 亚甲基) -2-B引哚酮 -6-甲酸三氘甲酯 (A)。
1H NMR (DMSO-d6, 400MHz); 2.00-2.35 (m,llH); 2.7 (s,2H); 3.06 (s,3H); 5.82 (d,lH); 6.87 (d,2H); 7.11 (d,2H); 7.17 (d,lH); 7.40-7.60 (m,6H); 10.94 (s,lH); 12.22 (s,lH); HRMS: 542.2710。
其中, 氯乙酸三氘甲酯的制备方法如下:
氯乙酸三氘甲酯的生产方法:将 5g的氯乙酰氯溶于 20mL干燥的二氯甲垸中, 0°C 下,
1.76g的氘代甲醇 (CD3OD) 缓慢加入到体系中, 搅拌 lh, 依次用水、 饱和碳酸氢钠溶液、 饱和食盐水洗, 无水硫酸钠干燥, 过滤, 减压蒸馏得到氯乙酸三氘甲酯。
氯乙酸三氘甲酯 HRMS: 111.0162。
实施例 2 化合物 B: (Z) -3- ( (4- (N-甲基 -2- (4-三氘甲基哌嗪 -1-取代) 乙酰氨基) 苯胺 基) (苯基) 亚甲基) -2-吲哚酮 -6-甲酸甲酯的制备
化合物 9-2的合成路线如下所示:
8-2 9-2
化合物 2-2: 间硝基苯甲酸甲酯的制备
2.0g间硝基苯甲酸(1-1 )加入到 10mL甲醇中, 加入 80mg 98wt%的浓硫酸, 于 100°C微 波反应 10分钟, 加入 100 mL CH2Cl2萃取, 依次用饱和 NaHC03和饱和食盐水洗涤, 无水 Na2S04干燥, 抽滤, 旋干, 得到产品化合物间硝基苯甲酸甲酯 (2-2) 1.95g, 收率为 88.5%。
1HNMR (CDC13, 400MHz ); 4.00 (s, 3H); 8.86 (s,lH); 8.40 (m,2H); 7.68 (t,lH); HRMS: 181.0360。
化合物 4-2: 4- (2-甲氧基 -2-乙酰基) -3-苯甲酸甲酯的制备
3.93g叔丁醇钾 (35mmol) 溶于 30mL DMF中, 冷却到 -10°C, 将溶于 5mL DMF的间硝 基苯甲酸甲酯 (2-2) (2.72g, 15mmol)和氯乙酸甲酯 (3-2) ( 1.84g, 16.5mmol) 的混合溶液 滴加到上述溶液中, 滴加完后, 在 -10°C条件下反应至 TLC检测不到原料, 反应液倒入冰水 (50mL) 与浓盐酸 (17mL) 的混合溶液中, 用乙酸乙酯萃取, 饱和食盐水洗, 干燥, 旋干。 柱层析分离, 得到化合物 4- (2-甲氧基 -2-乙酰基) -3-苯甲酸甲酯 (4-2) 粗品 2.36g。
化合物 5-2: 2-吲哚酮 -6-甲酸甲酯的制备
将 4- (2-甲氧基 -2-乙酰基) -3-苯甲酸甲酯 (4-2) ( 1.982g, 7.65mmol) 溶于 40mL乙酸 中,加入 250mg 10%的 Pd/C,在常压氢气压力下 40°C反应过夜。过滤除去催化剂,蒸去溶剂, 用少量乙酸乙酯洗涤产品, 过滤, 得到 0.61g (产率为 41%) 产品化合物 2-吲哚酮 -6-甲酸甲 酯 (5-2)。
1H NMR (CDC13,400 MHz); 3.56 (s,2H); 3.84 (s, 3H); 7.33 (s,lH)重叠到 7.34 (d,lH); 7.57 (d,lH) ; 10.53 (s,lH); HRMS:191.0586。
化合物 6-2: 1-氯乙酰基 -2-吲哚酮 -6-甲酸甲酯的制备
室温下, 2-吲哚酮 -6-甲酸甲酯 (5-2 ) (4.0g, 20.71mmol) 悬浮于 12mL的甲苯中, 将氯 乙酸酐 (5.4g,30.95mmol) 加入到上述悬浮液中, 加热回流 3h, 冷却到 80°C, 30min加入甲 基环己垸 (6mL), 悬浮液搅拌冷却到室温, 抽滤得到粗品, 用冷的甲醇 (4mL) 洗涤, 干燥 得白色固体 5.155g (93.5%), 即化合物 1-氯乙酰基 -2-吲哚酮 -6-甲酸甲酯 (6-2)。
1H NMR (DMSO-d6,400MHz); 8.66 (s,lH); 7.86 (d,lH); 7.52 (d,lH); 4.98 (s,2H);
3.95 (s, 3H); 3.88 (s,2H); HRMS: 267.0288。
化合物 8-2: (E) 小氯乙酰基 -3- (甲氧基 (苯基) 亚甲基) -2-吲哚酮 -6甲酸甲酯的制备 环境温度下, 1-氯乙酰基 -2-吲哚酮 -6-甲酸甲酯(6-2) ( 1.2g, 4.5mmol)悬浮于甲苯(6mL) 中,向其中加入乙酸酐(1.62g, 15.7mmol),体系加热到 110°C, lh内加入原苯甲酸三甲酯(7-1 ) (2.0g ,10.8mmol),继续反应 3h,易挥发产物挥发出去, 加入甲苯(4mL)保持体系浓度不变, 体系冷却到 5°C, 搅拌 lh, 抽滤得到粗品, 依次用甲苯、 甲苯与乙酸乙酯 (1 : 1 ) 的混合液 洗, 干燥得到 1.63g淡黄色固体即化合物 (E) -1-氯乙酰基 -3- (甲氧基 (苯基) 亚甲基) -2- 吲哚酮 -6甲酸甲酯 (8-2)。
1H NMR (DMSO-de, 400 MHz); 8.73 (d,lH); 8.09 (d,lH); 7.90 (dd,lH); 7.61-7.48 (m,5H); 4.85 (s,2H); 3.89 (s,3H); 3.78 (s,3H); HRMS:385.0715。
化合物 9-2: (E) -甲基 -3- (甲氧基 (苯基) 亚甲基) -2-吲哚酮 -6-甲酸甲酯的制备
溶有 KOH (41mg,0.6mmol) 的甲醇 ( 0.4mL) 溶液加入到 63°C的 (E) -1-氯乙酰基 -3- (甲氧基 (苯基) 亚甲基) -2-吲哚酮 -6 甲酸甲酯 (8-2) ( 800mg,2mmol) 的甲醇 3.2mL) 悬 浮液中,反应体系继续搅拌 30min,冷却到 0°C, 0°C下继续搅拌 2h, 抽滤, 甲醇洗涤, 干燥得 到 600mg (94.6%) 黄色固体即化合物 (E) -甲基 -3- (甲氧基 (苯基) 亚甲基) -2-吲哚酮 -6- 甲酸甲酯 (9-2)。
1H NMR (CDC13, 400 MHz); 8.08 (s,lH); 7.88 (d,lH); 7.75 (m,lH); 7.52-7.56 (m,3H); 7.40-7.45 (m,3H); 3.92 (s,3H); 3.74 (s,3H); HRMS:309.1005。
化合物 15-2
14-2 15-2 化合物 :12-1: 2-氯 甲基 (4-硝基苯基) 乙酰胺的制备
将 N-甲基 -4-硝基苯胺(10-1 ) (2.5g, 16.43mmol)加入乙酸乙酯 (3mL)中,加热到 60°C, 15分钟内加入氯乙酸酐 (11-1 ) (3.25g, 19mmol) 乙酸乙酯 ( 8mL) 溶液, 回流 lh, 降温到 75°C, 然后加入 10mL环己垸, 60°C结出晶体, 冷却到 0°C, 搅拌 lh, 过滤, 用环己垸洗涤, 干燥, 得到白色晶体 3.2g ( 85.2%) 即化合物 2-氯 -N-甲基 -N- (4-硝基苯基) 乙酰胺 (12-1 )。
1H NMR (DMSO-d6,400MHz); 8.29 (d,2H); 7.69 (d,2H); 4.35 (s,2H); 3.33 (s,3H); HRMS: 228.0322 c
化合物 :15-2: N- (4-氨基苯基) -N-甲基 -2- (4-三氘甲基哌嗪 -1-取代) 乙酰胺的制备
2g 2-氯 -N-甲基 -N- (4-硝基苯基) 乙酰胺 (12-1 ) 溶于 15mL甲苯中, 加热到 40°C, 在
30min内滴加 4-三氘甲基哌嗪 (13-2 ) (2.19g, 2.5eq), 加热搅拌 2h, 此时控制温度为 55°C, 搅拌完毕,降到室温,加入 5mL水洗,用 15mL异丙醇稀释甲苯的溶液体系,加入 100mg Pd/C
( 10%), 通入氢气 (4bar), 常温搅拌 3h, 过滤除去催化剂, 旋出溶剂, 残留物用乙酸乙酯 / 石油醚重结晶, 用石油醚洗涤, 干燥, 得到白色晶体 2.02g (产率为 88.0%) 即化合物 N- (4- 氨基苯基) -N-甲基 -2- (4-三氘甲基哌嗪 -1-取代) 乙酰胺 (15-2)。
1H NMR (DMSO-de, 400 MHz); 6.90 (d,2H); 6.65 (d,2H); 5.22 (2H); 3.04 (s,3H); 2.79 (s,2H); 2.32 (m,4H); 2.23 (m,4H); HRMS:265.1974。
化合 B的合成路线如下所示:
化合物 B: (Z) -3- ( (4- (N-甲基 -2- (4-三氘甲基哌嗪 -1-取代) 乙酰氨基) 苯胺基) (苯基) 亚甲基) -2-吲哚酮 -6-甲酸甲酯的制备
(E) -甲基 -3- (甲氧基 (苯基)亚甲基) -2-吲哚酮 -6-甲酸甲酯 (9-2) (200mg, 0.64mmol) 和 N- (4-氨基苯基) -N-甲基 -2- (4-三氘甲基哌嗪 -1-取代) 乙酰胺 ( 15-2) ( 171mg,0.65mmol) 的甲醇 (1.8mL) 悬浮液加热回流 8h, 缓慢冷却到 10°C, 10°C下继续搅拌 lh, 抽滤, 冷甲 醇洗, 干燥得 310mg ( 89%) 黄色固体即化合物 (Z) -3- ( (4- (N-甲基 -2- (4-三氘甲基哌嗪 小取代) 乙酰氨基) 苯胺基) (苯基) 亚甲基) -2-吲哚酮 -6-甲酸甲酯 (B)。
1H NMR (DMSO-de, 400 MHz); 2.00-2.35 (m,8 H); 2.7 (s,2H); 3.06 (s,3H); 3.76 (s, 3H); 5.82 (d,lH); 6.87 (d,2H); 7.11 (d,2H); 7.17 (d,lH); 7.40-7.60 (m,6H); 10.94 (s,lH); 12.22 (s,lH); HRMS: 542.2710。
将哌嗪 (1.0g, 11.6mmol) 和哌嗪盐酸盐 (1.845, 11.6mmol) 溶于乙醇 /氘代水 (5:1 ), 回流 1 小时, 冷却到 0°C。 滴加氘代碘甲垸 (0.85mL, 9.29mmol), 然后在环境温度下搅拌 90min, 体系温度降至 0°C后, 用 2mol/L的氢氧化钠水溶液调节 pH大概为 9.0。 萃取, 蒸馏, 收集 120-130 的产品, 得到无色液体 0.7g (产率 58.3%)。
1H NMR (CDCl3,400MHz); 2.69-2.71 (m,4H); 3.17-3.19 (m,4H); HRMS: 103.1180。 实施例 3 化合物 C: (Z) -3- ( (4- (N-甲基 -2- (4-三氘甲基哌嗪 -1-取代) 乙酰氨基) 苯胺 基) (苯基) 亚甲基) -2-吲哚酮 -6-甲酸三氘甲酯的制备
按实施例 1中所述的方法, 不同点在于: 用 4-三氘甲基哌嗪替换 4-甲基哌嗪, 从而制得 目标化合物, 其中, 4-三氘甲基哌嗪的合成方法按照实施例 2中所述。
实施例 4 化合物 D: (Z) -3- ( (4- (N-甲基 -2- (4-甲基哌嗪 -1-取代)乙酰氨基)苯胺基)(苯 基) 亚甲基) -2-吲哚酮 -6-甲酸二氘甲酯的制备
(Z) -3- ( (4- (N-甲基 -2- (4-甲基哌嗪 -1-取代) 乙酰氨基) 苯胺基) (苯基) 亚甲基) -2-B引哚酮 -6-甲酸二氘甲酯 (D) 的结构式如下所示:
按照实施例 1中所述的方法, 用 CD2HOH替换实施例 1中的 CD3OD, 用氯乙酸二氘甲 酯替换施例 1中的氯乙酸三氘甲酯进行制备。
其中,氯乙酸二氘甲酯的生产方法如下:将 5g的氯乙酰氯溶于 20mL干燥的二氯甲垸中, 0 V 下, 1.76g的 CD2HOH缓慢加入到体系中, 搅拌 lh, 依此用水、 饱和碳酸氢钠溶液、 饱 和食盐水洗, 无水硫酸钠干燥, 过滤, 减压蒸馏得到氯乙酸二氘甲酯; HRMS: 110.0114。 实施例 5 化合物 E: (Z) -3- ( (4- (N-甲基 -2- (4-甲基哌嗪 -1-取代) 乙酰氨基)苯胺基)(苯 基) 亚甲基) -2- (4,5,7-三氘吲哚酮) -6-甲酸甲酯的制备
(Z) -3- ( (4- (N-甲基 -2- (4-甲基哌嗪 -1-取代) 乙酰氨基) 苯胺基) (苯基) 亚甲基) -2- (4,5,7-三氘吲哚酮) -6-甲酸甲酯 (E) 的结构式如下所示:
按实施例 1中所述的方法, 不同点在于: 用 d4-间硝基苯甲酸代替间硝基苯甲酸, 换 d4-甲醇, 氯乙酸甲酯替换氯乙酸三氘甲酯, 从而制得目标化合物。
其中, D4-3-硝基苯甲酸的合成方法如下:
将 1.5g的 3-氨基苯甲酸, 150mg的 10% Pd/C, 重水 60mL, 加入到 200mg的高压反应釜 中, 氮气交换三次, 氢气交换三次, 使高压反应釜中充满常压氢气, 180°C反应 24小时。 过 滤除去 Pd/C催化剂, 减压除去重水即可得到 D4-3-甲基苯胺。 8 °C下, 5-20%的丙酮水溶液 与 4当量的以碳酸氢钠做缓冲的过氧单磺酸钾溶液同时加入到 D4-3-甲基苯胺中, TLC检测反 应进度, 反应完成后, 用乙酸乙酯萃取, 干燥, 旋干, 硅胶柱纯化得到 D4-3-硝基苯甲酸; HRMS:171.0477 o
实施例 6 化合物 F: (Z) -3- ( (4- (N-甲基 -2- (4-甲基 -2, 3, 5, 6-八氘哌嗪 -1-取代) 乙酰 氨基) 苯胺基) (苯基) 亚甲基) -2-吲哚酮 -6-甲酸甲酯的制备
(Z) -3- ( (4- (N-甲基 -2- (4-甲基 -2, 3, 5, 6-八氘哌嗪小取代) 乙酰氨基) 苯胺基) (苯基) 亚甲基) -2-B引哚酮 -6-甲酸甲酯 (F) 的结构式如下所示:
按实施例 1中所述的方法, 不同点在于: 用 N-甲基 -2, 3, 5, 6-八氘哌嗪代替 N-甲基哌 嗪, 甲醇替换 d4-甲醇, 氯乙酸甲酯替换氯乙酸三氘甲酯, 从而制得目标化合物。 其中, N- 甲基 -2, 3, 5, 6-八氘哌嗪为市售的。
实施例 7 化合物 G: (Z) -3- ( (4- (N-甲基 -2- (4-甲基哌嗪 -1-取代) 二氘乙酰氨基) 苯胺 基) (苯基) 亚甲基) -2-B引哚酮 -6-甲酸甲酯的制备
(Z) -3- ( (4- (N-甲基 -2- (4-甲基哌嗪 -1-取代) 二氘乙酰氨基) 苯胺基) (苯基) 亚甲 基) -2-吲哚酮 -6-甲酸甲酯 (G) 的结构式如下所示:
按实施例 1 中所述的方法, 不同点在于: 用氯二氘乙酰氯代替氯乙酰氯, 甲醇替换 d4- 甲醇, 氯乙酸甲酯替换氯乙酸三氘甲酯, 从而制得目标化合物。 氯二氘乙酰氯来源为市售。 实施例 8 化合物 H: (Z) -3- ( (4- (N-甲基 -2- (4-甲基哌嗪 -1-取代)乙酰氨基)苯胺基)(2,
3, 4, 5, 6-五氘苯基) 亚甲基) -2-吲哚酮 -6-甲酸甲酯的制备
( Z) -3- ( ( 4- (N-甲基 -2- ( 4-甲基哌嗪 -1-取代) 乙酰氨基) 苯胺基) (2, 3, 4, 5, 6- 五氘苯基) 亚甲基) -2-B引哚酮 - -甲酸甲酯 (H) 的结构式如下所示:
按实施例 1中所述的方法, 不同点在于: 用原五氘苯甲酸三甲酯代替原苯甲酸三甲酉 ί 甲醇替换 d4-甲醇, 氯乙酸甲酯替换氯乙酸三氘甲酯, 从而制得目标化合物。
原五氘苯甲酸三甲酯制备方法参考以下文献:
苯胺的氘代参考 Hironao Sajiki et al, Tetrahedron Letters 46 (2005 ) 6995-6998; 氘代苯 胺的氨基转换成溴参考 Itsuro Shimada, Bioorganic & Medicinal Chemistry 16 ( 2008 ) 3309-3320; 原五氘苯甲酸三甲酯的制备参考 By Kantlehner, Willi et al .Synthesis, 1981 ( 5 ) , 380-381; 原五氘苯甲酸三甲酯 HRMS: 187.1259o
实施例 9 化合物 I: (Z) -3- ( ( 4- ( N-三氘甲基 -2- (4-甲基哌嗪 -1-取代) 乙酰氨基)苯胺基) (苯基) 亚甲基) -2-Π引哚酮 -6-甲酸甲酯的制备
(Z) -3- ( (4- (N-三氘甲基 -2- (4-甲基哌嗪小取代) 乙酰氨基) 苯胺基) (苯基) 亚甲 基) -2-吲哚酮 -6-甲酸甲酯 (I)
按实施例 1中所述的方法,不同点在于:用 N-三氘甲基对硝基苯胺代替 N-甲基对硝基苯 胺, 甲醇替换 d4-甲醇, 氯乙酸甲酯替换氯乙酸三氘甲酯, 从而制得目标化合物。
N-三氘甲基对硝基苯胺的合成路线参照 Ullmann amination参考文献 Jiao Jiao. J. Org. Chem.2011, 76, 1180-1183。 N-三氘甲基对硝基苯胺 HRMS: 155.0776。
实施例 10 化合物 J: (Z) -3- ( (4- (N-甲基 -2- (4-甲基哌嗪 -1-取代) 乙酰氨基) -2,3,5,6- 四氘苯胺基) (苯基) 亚甲基) -2-吲哚酮 -6-甲酸甲酯的制备
(Z) -3- ( (4- (N-甲基 -2- (4-甲基哌嗪小取代) 乙酰氨基) -2,3,5,6-四氘苯胺基) (苯基) 亚甲基) -2-吲哚酮 -6-甲酸甲酯 (J) 的结构式如下所示:
按实施例 1中所述的方法,不同点在于:用 N-甲基对硝基四氘苯胺代替 N-甲基对硝基苯 甲醇替换 d4-甲醇, 氯乙酸甲酯替换氯乙酸三氘甲酯, 从而制得目标化合物。
合成步骤参考文献:
苯环上硝基参照 Alwyn Spencer.Journal of Organometallic Chemistry,295 ( 1985 ) 199-210; 氨基转换成溴参照 Itsuro Shimada, Bioorganic & Medicinal Chemistry 16 (2008 ) 3309-3320; N-甲基对硝基四氘苯胺的合成参照 Ullmann amination 参考文献 Jiao Jiao. J. Org.Chem.2011,76, 1180- 1183 ; N-甲基对硝基四氘苯胺 HRMS: 156.0846。
实施例 11 化合物 K: ( Z) 7-氘 -3- ( (4- (N-甲基 -2- (4-三氘甲基哌嗪 -1-取代) 乙酰氨基) 苯胺基) (苯基) 亚甲基) -2-吲哚酮 -6-甲酸甲酯的制备
按照实施例 1所述方法, 其中采用化合物 2-氘 -3硝基苯甲酸代替化合物间硝基苯甲酸, 甲醇代替 d4- 甲醇, 氯乙酸甲酯替换氯乙酸三氘甲酯。
在干燥氮气氛围下, 7.2mmol 的 2-溴 -3-硝基苯甲酸, 21g4.8%的钠汞齐, 在 MeOD (10 mL) 与 D20 (5mL) 的混合溶液中回流 3小时, 冷却后, 轻轻倒出, 用甲醇洗涤钠汞齐, 旋 干甲醇溶液, 用 10%的盐酸酸化剩余物, 乙醚萃取, 饱和食盐水洗, 无水硫酸镁干燥, 过滤 并除去溶剂得到 2-氘 -3硝基苯甲酸; HRMS:168.0289。
实施例 12 化合物 L: (Z) -3- ((4- (N-甲基 -2- (4-甲基 -2, 6-四氘哌嗪 -1-取代) 乙酰氨基) 苯胺基) (苯基) 亚甲基) -2-吲哚酮 -6-甲酸甲酯的制备
化合物 L的结构式如下所示:
按照实施例 1所述方法,其中采用甲醇代替 d4- 甲醇,氯乙酸甲酯替换氯乙酸三氘甲酉 ί 甲基 (3,3,5,5-D4) 哌嗪代替 4-甲基哌嗪。
4-甲基哌嗪 -2,6-二酮 (1.28 g, lOmmol) 的四氢呋喃溶液 (25mL) 在一小时内加入到含 有氘化铝锂 (1.26g,30mmol) 的四氢呋喃溶液中, 回流四小时, 冷却, 缓慢加入水, 用乙 醚萃取数次,干燥乙醚层,旋干,蒸馏得到纯的 1-甲基 (3,3,5, 5-D4) 哌嗪; HRMS:104.1259。
实施例 13 化合物体外激酶抑制实验
利用迁移分析(Mobility Shift Assay)法在 Km ATP的情况下,检测 4个化合物(Nintedanib、 化合物 A、 化合物 B、 化合物 C) 对激酶 FGFR-1 , KDR, PDGFR-α的抑制活性。
实验中, 本发明发明人对体外 3个激酶 FGFR-1 , KDR, PDGFR-a进行化合物的筛选, 每个化合物从 lOuM起始, 3倍稀释, 10个浓度点进行检测 (2复孔) , 采用化合物十字孢碱 (staurosporine) 作为标准对照。
Km ATP 表示在激酶与 ATP最大反应速度一半时对应的 ATP浓度。
实验材料:
以下材料由尚华集团购买:
KDR ( from Carna, Cat. No. 08-191, Lot. No. 07CBS-0540)
FGFR1 ( from Carna, Cat. No. 08-133, Lot. No. 09CBS-0989)
FGFR3 ( from Carna, Cat. No. 08-135, Lot. No. 06CBS-3177)
PDGFRa ( from Invitrogen , Cat. No. PR7346A, Lot. No. 682476L)
ATP ( from Sigma, Cat. No. A7699-1G, CAS No. 987-65-5 )
DMSO ( from Sigma, Cat. No. D2650, Lot. No. 474382 )
EDTA ( from Sigma, Cat. No. E5134, CAS No. 60-00-4) . 96-well plate ( from Corning, Cat. No. 3365, Lot. No. 22008026)
384-well plate ( from Corning, Cat. No. 3573, Lot. No. 12608008 )
实验方法:
Mobility shift assay
I、 配制 lx的激酶缓冲液和终止液
1、 缓冲液
50mM/L HEPES, pH7.5 ;
0.0015% Brij-35; 0.015%为体积百分数, S卩 1L缓冲液中含 0.00015L Brij-35;
lOmM/L MgCl2;
2mM/L DTT;
2、 终止液
100 mM/L HEPES, pH 7.5;
0.015% Brij-35; 0.015%为体积百分数, S卩 1L终止液中含 0.00015L Brij-35;
0.2% Coating Reagent #3; 0.2%为体积百分数, S卩 1L终止液中含 0.002L Coating Reagent
#3;
50 mM/L EDTA;
mM/L 指每升目标液中物质的浓度。 如终止液中 100 mM/L HEPES 指 1L 终止液中 HEPES的浓度为 100mmol/L。
II. 化合物配制
1 ) 化合物稀释
3、供试化合物分别用 100% DMSO 溶解成 10mM的浓度。化合物检测终浓度为 10 μΜ。 首先配置成 50倍浓度, 即 500uM。
4、 在 96孔板中 A行第 2个孔加入 ΙΟΟμί 500μΜ上述步骤 3稀释的化合物, 3倍稀释该 化合物, 共 10个浓度。 具体操作如下:
除第 2个孔以外每个孔加入 60μί 100% DMSO, 从第 2个孔中取 30μί化合物到第 3个 孔, 依次类推, 稀释到第 11孔, 共 10个浓度。
2) 转移 5倍化合物到反应板
5、 从上述 96孔板的每一孔取 10 μL到另一块 96孔板中, 加入 90 μL lx的激酶缓冲液。 因此, 化合物溶解于体积浓度为 10%的 DMSO中。 在振板机上振荡 10分钟, 混匀。
6、 从上述 96孔板中取出 5 μL到一块 384孔反应板。每行设阴性对照孔和阳性对照孔各 2个。 96孔板中 A行化合物以左右复孔的形式转入 384孔板 A行第 13〜24孔。 因此, 384 孔反应板中就有 5μί的体积浓度为 10% DMSO溶解的 5倍化合物, 即未加 2.5倍激酶溶液和 2.5倍底物溶液时, 384孔板中化合物浓度为 50mM/L。
III. 激酶反应
1 ) 配制 2.5倍酶溶液
7、 以浓度(单位是激酶的效价) 2.5倍的激酶, 加入到 1倍体积的激酶缓冲液中得到 2.5 倍的缓冲液;
2) 配制 2.5倍的底物溶液
8、 与浓度为 (单位是激酶的效价) 2.5倍的激酶相对应浓度的底物 "FAM标记的多肽和
ATP", 加入到 1倍体积的激酶缓冲液中得到 2.5倍的底物溶液;
3 ) 向 384孔板中加入酶溶液
9、 384孔反应板中已有 5μί 的体积浓度为 10% 的 DMSO溶解的 5倍化合物;
10、 在 384孔反应板中加入 ΙΟμί的 2.5倍酶溶液;
11、 室温下孵育 10分钟;
4) 向 384孔板中加入底物溶液
12、 在 384孔反应板中加入 ΙΟμί的 2.5倍底物溶液;
5 ) 激酶反应和终止
13、 28°C下孵育一定时间 (由各个激酶决定);
14、 加 25 μL终止液终止反应;
IV. Caliper读取数;
15、 Caliper上读取转化率数据;
V. 抑制率计算
16、 从 Caliper上复制转化率数据;
17、 把转化率转化成抑制率数据。 其中 max是指 DMSO对照的转化率, min是指无酶活 对照的转化率; Conversion是指加有化合物、 激酶溶液和底物溶液三者的反应孔的转化率。
百分抑制率 ( Percent inhibition) = ( max-conversion) I ( max-min) * 100
VI.体外激酶抑制实验结果见表 1
表 1 Nintedanib、 化合物 B、 化合物 A、 化合物 C的 IC5Q 检测结果
表 1中 IC5Q的单位 nM/L。
体外激酶活性检测表明, 化合物 A、 B、 C的激酶活性与 Nintedanib接近, 其原因是化合 物八、 B、 C是在 Nintedanib的结构基础上将特定位点的氢替代为氘。 从碳氢键变为碳氘键并 未改变化合物的空间结构和排布,从而对化合物与血管生长因子(KDR, FGFR-1 , PDGFR-α) 之间的偶联不构成较大影响。
实施例 14 药代动力学研究实验
将化合物 Nintedanib ( BIBF 1120 ) 化合物 A、 化合物 B和化合物 C进行药代动力学实 验。
小鼠分别灌胃给予 Nintedanib、 化合物 A、 化合物 B和化合物 C, 采集不同时间点全血 样品, 分离血浆, 以液相色谱一串联质谱法测定血浆中总的药物浓度。
1、 给药方案
健康 Balb/c小鼠, 雄性, 体重 18〜20g。 分别单次灌胃给予 50mg/mL的 Nintedanib、 化 合物 A、 化合物 B、 化合物 C, 化合物以 0.5% (w/v)羟丙基甲基纤维素溶液溶解, 给药体积 为 10mL/kg。 给药前禁食 12h, 自由饮水。 给药 6h后统一进食。 于给药后 0.5、 1.0、 2.0、 4.0、 6.0和 24.0h,每个时点 3只小鼠,经小鼠眼球后静脉丛取血 0.3mL,置肝素化试管中, 3500rpm 离心 10min, 分离血浆, 于 -80 °C冰箱中冻存。
2、 液相色谱一串联质谱检测方法
LC— MS/MS样品分析方法流动相
流动相 A: 乙腈
流动相 B : 0.1mol/L乙酸铵水溶液 (使用浓氨水调 pH至 8.5 )
按体积比 A ( 70%), B ( 30%);
3、 药代动力学实验结果如下:
小鼠单次灌胃给予浓度为 50mg/mL, 给药体积 10mL/kg的 Nintedanib、 化合物 A、 化 合物 B、 化合物 C后小鼠血药浓度 -时间曲线见图 1, 图 2, 图 3, 图 4, 图 5。
小鼠单次灌胃给予浓度为 50mg/mL, 给药体积 10mL/kg的 Nintedanib、 化合物 A、 化合 物 B、 化合物 C后的药代动力学参数见表 2。
表 2
由实验结果可见, 化合物 B较 Nintedanib、 化合物 A、 化合物 C在小鼠体内有较高的血 药浓度, 化合物 C 的体内血药浓度略微低于 Nintedanib, 化合物 A体内血药浓度明显低于 Nintedanib
原因是: 将 Nintedanib吲哚环上甲氧基和哌嗪环上氮甲基都进行氘代所得化合物 C并未 减弱 CYP 450的代谢作用,因此其体内药代动力学参数略微低于 Nintedanib但与之相差较少。 将 Nintedanib吲哚环上甲氧基进行氘代所得化合物 A, 其小鼠体内药代动力学参数明显低于 Nintedanib, 原因是甲氧基氘代后降低了药物在小鼠体内的吸收。将 Nintedanib哌嗪环上氮甲 基进行氘代所得化合物 B,其小鼠体内药代动力学参数明显优于 Nintedanib,原因是哌嗪环上 氮甲基的氘代减弱或阻断了相应代谢酶对化合物 B 的代谢作用, 使其血药浓度高于 Nintedanib, 在体内停留时间得以延长, 整体药代动力学参数优于 Nintedanib; 哌嗪环上氮垸 基的氘代会减弱或阻断了相应代谢酶对化合物的代谢作用,从而延长化合物在体内停留时间。 实施例 15 BIBF 1120与化合物 B在体内抗肿瘤活性研究
FaDu在 RPMI 1640+10%FBS培养基中培养;当对数生长期的细胞汇合度达到 80%— 90% 的时候, 使用胰酶消化, 离心, 并用双无的培养基洗涤细胞三次, 再计数, 最后细胞用双无 的培养基重悬。 在进行皮下模型构建时, 按照每只裸鼠接种 5*10ό个 /ΙΟΟ μί的浓度接种于裸 鼠右侧后背部皮下。 接种后 15天, 当平均的肿瘤体积达到 100 150mm3时, 对老鼠进行随 机分组, 每个组 7只, 分别为溶剂对照组, 化合物 B (50 mg/kg), 化合物 B (25 mg/kg), 化 合物 B ( 12.5 mg/kg), 化合物 BIBF 1120 (25 mg/kg)。 药物给药方式为灌胃口服, 频率为 一天一次, 周期为 27天, 每三天进行一次肿瘤体积测量。
最终,得到肿瘤体积生长曲线如图 6所示, 图 6中化合物 B的浓度为 50 mg/kg 时抑制率 为 97.4%;浓度为 25 mg/kg时抑制率为 87.9%;浓度为 12.5mg/kg时抑制率为 63.0%; BIBF 1120 浓度为 25mg/kg时抑制率为 82.3%。 表明给药浓度 25mg/kg时, 化合物 B比阳性对照化合物 BIBF 1120的抑制率略好; 给药浓度 50mg/kg时, 肿瘤基本被抑制住生长。
小鼠体重变化曲线如图 7所示。 图 7小鼠体重变化曲线表明: 化合物 B在 3个不同给药 剂量组下, 体重下降均较阳性对照给药组 BIBF 1120大, 表明化合物 B体内毒性较阳性对照 化合物 BIBF 1120大。
图 6、 图 7中 vehicle具体是溶媒对照组, 即给 0.5 %的羟乙基纤维素。
FaDu细胞株购买于美国典型物种保存中心 (American Type culture collection,ATCC); 化 合物 B和 BIBF 1120由四川大学生物治疗国家重点实验室合成; RPMI-1640培养基购买于赛 默飞世尔公司; FBS胎牛血清购买于 Gibco公司; 胰酶购买于英韦创津公司; 青链霉素购买 于大连宝生物公司; 配制药物的溶剂羟乙基纤维素 (4,500-6,500mPa.S) TCI公司; 所需 SPF 级 BALB/c裸鼠购买于北京华阜康生物科技有限公司, 5 6周龄, 体重 18 20g, 全部为雌 性。
Claims
1、 通式 (a) 所示吲哚酮化合物
R2、 R3、 R4、 R5、 R^、 R7、 R8、 !¾、 R10、 Rn> R12、 R13、 R14、 R15、 R16、 R17、 R18、 Ri9 > R2o R2i R22或 R23每一个独立表示 H或 D;
式 (a) 所示化合物至少有一个 D。
2、 根据权利要求 1所述的吲哚酮化合物, 其特征在于: R2、 R3、 、 R5、 、 R7、 、
R9 Rl0 Rll > Rl2 Rl3 Rl4 Rl5 Rl6 Rl7 Rl8 Rl9 ^20、 R^21、 R22或 R23每 ~ "个独 表 示 H, 其结构式如下通式 (b) 所示:
3、 根据权利要求 2所述的吲哚酮化合物, 其特征在于 R24为未氘代的、 一次或多次氘 代的或全氘代的 〜 垸基。
4、 根据权利要求 3所述的吲哚酮化合物, 其特征在于 R24为一次或多次氘代的或全氘 代的 〜C4垸基。
5、 根据权利要求 4所述的吲哚酮化合物, 其特征在于 R24为一次或多次氘代的或全氘 代的 〜C2垸基。
6、 根据权利要求 5所述的吲哚酮化合物, 其特征在于: R24为 -CH2D、 -CHD2或 -CD3。
( C)。
8、 根据权利要求 7所述的吲哚酮化合物, 其特征在于: 为未氘代的、 一次或多次氘 代的或全氘代的 〜 垸基。
9、 根据权利要求 8所述的吲哚酮化合物, 其特征在于: 为未氘代的 〜 垸基。
10、 根据权利要求 9所述的吲哚酮化合物, 其特征在于: 为 ¾、 -CH2CH3、 - (CH2) 2CH3或- (CH2) 3CH3。
11、 根据权利要求 10所述的吲哚酮化合物, 其特征在于: 为 ¾或 -CH2CH3。
12、 根据权利要求 11 所述的吲哚酮化合物, 其特征在于: 为 -CH3 ; 其结构式如下通 式 (d) 所示:
(d)。
13、 根据权利要求 12所述的吲哚酮化合物, 其特征在于: R25为未氘代的、 一次或多次 氘代的或全氘代的 〜 垸基。
14、 根据权利要求 13所述的吲哚酮化合物, 其特征在于: R25为未氘代的 〜 垸基。
15、根据权利要求 14所述的吲哚酮化合物,其特征在于: R25为 -CH3、 -CH2CH3、 - (CH2) 2CH3或- (CH2) 3CH3。
16、 根据权利要求 15所述的吲哚酮化合物, 其特征在于: R25为 -CH3或 -CH2CH3。
17、 根据权利要求 1所述的吲哚酮化合物, 其特征在于: 所述化合物为:
18、 权利要求 1〜17任一项所述的吲哚酮化合物的各种晶型、 其药学上可接受的盐或其 溶剂化合物。
19、 预防或治疗癌症的药物, 其特征在于: 其活性成分包含权利要求 1〜17任一项所述 的吲哚酮化合物或权利要求 18所述的吲哚酮化合物的各种晶型、其药学上可接受的盐或其溶 剂化合物。
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