CN111138459B - Optical isomer of FGFR4 inhibitor and application thereof - Google Patents
Optical isomer of FGFR4 inhibitor and application thereof Download PDFInfo
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- CN111138459B CN111138459B CN201911071553.5A CN201911071553A CN111138459B CN 111138459 B CN111138459 B CN 111138459B CN 201911071553 A CN201911071553 A CN 201911071553A CN 111138459 B CN111138459 B CN 111138459B
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- A61P35/02—Antineoplastic agents specific for leukemia
Abstract
The invention belongs to the field of medicinal chemistry, relates to optical isomers of an FGFR4 inhibitor and application thereof, and particularly provides optical isomers shown in a formula I or a formula II or hydrates, solvates, crystals or pharmaceutically acceptable salts thereof, a preparation method thereof, pharmaceutical compositions containing the optical isomers or the hydrates, the solvates, the crystals or the pharmaceutically acceptable salts thereof, and application of the optical isomers or the hydrates, the solvates, the crystals or the pharmaceutically acceptable salts thereof in treating tumors. The compound of the invention has good inhibitory activity on FGFR4, is very hopeful to become a tumor therapeutic agent with higher curative effect and smaller side effect,
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to optical isomers of an FGFR4 inhibitor, hydrates, solvates, crystals or pharmaceutically acceptable salts thereof, a preparation method thereof, pharmaceutical compositions containing the compounds and application of the compounds or the compositions in treating tumors.
Background
The receptor tyrosine kinase plays a key role in various links such as tumorigenesis development, invasion and metastasis, drug resistance and the like due to abnormal expression activation or gene mutation, and becomes an important target for research and development of antitumor drugs. Fibroblast Growth Factor Receptors (FGFRs) are important members of the receptor tyrosine kinase family, mainly including four subtypes FGFR1, FGFR2, FGFR3 and FGFR 4. The ligand is Fibroblast Growth Factors (FGFs). These receptors form ternary complexes with FGFs and Heparan Sulfate Proteoglycans (HSPGs), which in turn trigger a series of signaling and participate in the regulation of various physiological and pathological processes in the organism.
The amino acid sequences of FGFR family members (FGFR 1, FGFR2, FGFR3, and FGFR 4) are highly conserved and differ in ligand affinity and tissue distribution. Due to gene amplification, mutation, fusion or ligand induction and the like, all the FGFR members are continuously activated to induce the proliferation, invasion and migration of tumor cells, promote angiogenesis and promote the generation and development of tumors. FGFRs are highly expressed and abnormally activated in various tumors and are closely related to poor prognosis of tumor patients, such as non-small cell lung cancer, breast cancer, gastric cancer, bladder cancer, endometrial cancer, prostate cancer, cervical cancer, colon cancer, esophageal cancer, keratinocyte tumor, myeloma, rhabdomyosarcoma and the like. Fibroblast growth factor receptor 4 (FGFR 4) is a member of the fibroblast growth factor receptor family, encoded by the FGFR4 gene, and the FGFR4 genomic structure contains 18 exons. Ectopic mineralization was observed in rats treated with FGFR1 inhibitors, showing inappropriate calcium phosphorus deposition in soft tissues (Brown, AP et al (2005), toxicol. Pathol, pages 449-455). This suggests that selective inhibition of FGFR4 to avoid certain toxicities is desirable. The research finds that FGFR4 is the only receptor with specificity shown by FGF19 (the physiological ligand of FGFR 4), and the over-expression of FGF19 can cause the FGF19-FGFR4 pathway to be activated, thereby causing some cancers such as sarcoma, renal cell carcinoma, breast cancer, liver cancer and the like. FGFR4 inhibitor therapy is effective against tumors with FGF19 gene amplification. Ectopic mineralization was observed in rats treated with FGFR1 inhibitors and characterized by inappropriate calcium phosphorus deposition in soft tissues (Brown, AP et al (2005), toxicol. Pathol, pages 449-455). This suggests that selective inhibition of FGFR4, while not inhibiting other subtypes of FGFR, such as FGFR1, may avoid certain toxic side effects of the drug. Presently, a range of FGFR4 inhibitors is disclosed, including the compounds disclosed in WO2015/108992, WO2015/059668, WO2015061572, and the like. There is still a need to develop compounds with better potency, less toxicity and higher selectivity.
Furthermore, a large body of literature data suggests that optical isomers of chiral drugs have different pharmacodynamic, pharmacokinetic and toxicological properties. In the prior period, a series of pharmacological researches show that the FGFR4 inhibitor has good drug forming property, so that the research on synthesizing optical isomers and carrying out biological activity, toxicity and side effect on the optical isomers has important guiding significance on the research on the drug forming property of the compounds, and is worthy of deep development.
Disclosure of Invention
An object of the present invention is to provide an optical isomer having FGFR4 inhibitory activity represented by formula I or formula II, or a hydrate, solvate, crystal or pharmaceutically acceptable salt thereof,
another object of the present invention is to provide a method for preparing the optical isomer represented by formula I or formula II of the present invention or a hydrate, solvate, crystal or pharmaceutically acceptable salt thereof.
Still another object of the present invention is to provide a composition comprising the optical isomer represented by formula I or formula II of the present invention or a hydrate, solvate, crystal or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, and a composition comprising the optical isomer represented by formula I or formula II of the present invention or a hydrate, solvate, crystal or pharmaceutically acceptable salt thereof and another FGFR4 inhibitor or inhibitors.
The invention also provides a method for treating tumors by using the optical isomer shown in the formula I or the formula II or the hydrate, the solvate, the crystal or the pharmaceutically acceptable salt thereof, and an application of the optical isomer shown in the formula I or the formula II or the hydrate, the solvate, the crystal or the pharmaceutically acceptable salt thereof in preparing a medicament for treating tumors.
Aiming at the purpose, the invention provides the following technical scheme:
in a first aspect, the present invention provides an optical isomer represented by formula I or formula II, or a hydrate, solvate, crystal or pharmaceutically acceptable salt thereof:
in some embodiments, the compounds of formula I or II of the present invention are in substantially pure isomeric form, having an isomeric purity of at least 60% EE. In a particular embodiment, the isomer purity of the compounds of formula I or II of the present invention is at least 90% EE. In another specific embodiment, the compounds of formula I or II of the invention have an isomer purity of at least 98% ee. In a preferred embodiment, the compounds of formula I or II of the invention have an isomeric purity of at least 99% EE. The isomer excess value provides a quantitative measure of the percentage of the major isomer over the percentage of the minor isomer present therewith, and can be readily measured by appropriate methods established and well known in the art, such as chiral High Pressure Liquid Chromatography (HPLC), chiral Gas Chromatography (GC), nuclear Magnetic Resonance (NMR) using chiral shift reagents, and the like.
In some preferred embodiments, the present invention provides pharmaceutically acceptable salts of compounds of formula I or formula II, wherein the salt is a pharmaceutically acceptable salt of the compound with an acid including, but not limited to, phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid, citric acid, maleic acid, hydroxymaleic acid, propionic acid, glycolic acid, stearic acid, malonic acid, mandelic acid, succinic acid, fumaric acid, lactic acid, acetic acid, trifluoroacetic acid, glutamic acid, malic acid, tartaric acid, ascorbic acid, pamoic acid, benzoic acid, phenylacetic acid, glutamic acid, salicylic acid, oxalic acid, fumaric acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, hydroxyethanesulfonic acid, and the like.
In another aspect, the present invention provides a method for preparing an optical isomer represented by formula I or formula II of the present invention, or a hydrate, solvate, crystal or pharmaceutically acceptable salt thereof, comprising:
(1) Reacting a compound of formula i with a compound of formula ii or a salt thereof under basic conditions to produce a compound of formula iii;
(2) The compound of formula iii is reacted under conventional reaction conditions to produce a compound of formula iv;
(3) Reacting the compound shown in the formula iv with the compound shown in the formula v through palladium mediated coupling reaction to obtain a compound shown in the formula vi;
(4) Reducing the nitro group on the compound of the formula vi into amino group through reduction reaction to obtain a compound of a formula vii;
(5) Reacting the compound of the formula vii with a compound of the formula viii by amide coupling reaction to obtain a compound of the formula viii;
wherein the dotted line
Is shown as
Or
LG 1 、LG 2 Represents a leaving group, which may be the same or different, preferably halogen or sulfonyloxy, more preferably Cl, br, I;
m may be-B (OR) 1 ) 2 -Sn (alkyl) or-Zn-halo-, wherein R 1 Is H or alkyl, preferably methyl;
x is halogen, preferably bromine.
In another aspect, the present invention provides a method for preparing an optical isomer represented by formula I or formula II of the present invention, or a hydrate, solvate, crystal or pharmaceutically acceptable salt thereof, comprising:
in a third aspect, the present invention provides a pharmaceutical composition comprising an optical isomer represented by formula I or formula II of the present invention or a hydrate, solvate, crystal or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
In some embodiments, the present invention provides a pharmaceutical composition comprising an optical isomer represented by formula I or formula II of the present invention or a hydrate, solvate, crystal or pharmaceutically acceptable salt thereof, further comprising one or more selected from the group consisting of: FGFR inhibitors, FGFR4 inhibitors, PI3K inhibitors, tyrosine protease inhibitors, EGFR inhibitors, VEGFR inhibitors, bcr-Abl inhibitors, c-kit inhibitors, c-Met inhibitors, raf inhibitors, MEK inhibitors, histone deacetylase inhibitors, VEGF antibodies, EGF antibodies, HIV protein kinase inhibitors, HMG-CoA reductase inhibitors, and the like.
The optical isomer represented by formula I or formula II of the present invention or a hydrate, solvate, crystal or pharmaceutically acceptable salt thereof may be mixed with a pharmaceutically acceptable carrier, diluent or excipient to prepare a pharmaceutical preparation suitable for oral or parenteral administration. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes. The formulations may be administered by any route, for example by infusion or bolus injection, by a route of absorption through epithelial or cutaneous mucosa (e.g. oral mucosa or rectum, etc.). Administration may be systemic or local. Examples of the formulation for oral administration include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like. The formulations may be prepared by methods known in the art and include carriers, diluents or excipients conventionally used in the art of pharmaceutical formulation.
According to the present invention, in some embodiments, the present invention provides a compound of formula a, or a hydrate, solvate, crystal or pharmaceutically acceptable salt thereof,
wherein the compound of formula a or a hydrate, solvate, crystal or pharmaceutically acceptable salt thereof is enriched in the optical isomer of formula I or a hydrate, solvate, crystal or pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula a, or a hydrate, solvate, crystal or pharmaceutically acceptable salt thereof, of the present invention contains a substantially pure optical isomer of formula I, or a hydrate, solvate, crystal or pharmaceutically acceptable salt thereof. In a particular embodiment, the compound of formula a or a hydrate, solvate, crystal or pharmaceutically acceptable salt thereof of the present invention contains more than 60% of the optical isomer of formula I or a hydrate, solvate, crystal or pharmaceutically acceptable salt thereof. In another specific embodiment, the compound of formula a or a hydrate, solvate, crystal or pharmaceutically acceptable salt thereof of the present invention contains greater than 90% of the optical isomer of formula I or a hydrate, solvate, crystal or pharmaceutically acceptable salt thereof. In another specific embodiment, the compound of formula a or a hydrate, solvate, crystal or pharmaceutically acceptable salt thereof of the present invention contains greater than 98% of the optical isomer of formula I or a hydrate, solvate, crystal or pharmaceutically acceptable salt thereof. In a preferred embodiment, the compound of formula a or a hydrate, solvate, crystal or pharmaceutically acceptable salt thereof of the present invention contains more than 99% of the optical isomer of formula I or a hydrate, solvate, crystal or pharmaceutically acceptable salt thereof.
In some embodiments, the compounds of formula a of the present invention are in substantially pure isomeric forms that are substantially free of other isomers. For example, in one embodiment, the compounds of formula a of the present invention are substantially free of the isomer of formula II. In another embodiment, the compounds of formula a of the present invention are in pure isomeric form.
In a fourth aspect, the present invention provides the use of an optical isomer of formula I or formula II, or a hydrate, solvate, crystal or pharmaceutically acceptable salt thereof, a compound of formula a, or a hydrate, solvate, crystal or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the treatment of a tumor, preferably a method for the treatment and/or prevention of a disease or condition mediated by FGFR-4 or FGF19 and for the manufacture of a medicament for the treatment and/or prevention of a disease or condition mediated by FGFR-4 or FGF19, characterized in that FGFR-4 or FGF19 overexpression, FGFR4 or FGF19 amplification, is characteristic in an individual. In a preferred embodiment, the invention provides a method for treating and/or preventing tumors by using the compound shown in formula I, formula II or formula III or pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof or the pharmaceutical composition of the invention, and application of the compound in preparing medicaments for treating and/or preventing tumors, wherein the tumors are mediated by FGFR 4. In a preferred embodiment, the invention relates to a method for treating and/or preventing tumors by using an optical isomer shown in formula I or formula II or a hydrate, a solvate, a crystal or a pharmaceutically acceptable salt thereof, a compound shown in formula A or a hydrate, a solvate, a crystal or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the compound and the hydrate, the solvate, the crystal or the pharmaceutically acceptable salt thereof, and application of the compound in preparing medicaments for treating and/or preventing tumors, wherein the tumors are selected from breast cancer, ovarian cancer, lung cancer, liver cancer and sarcoma. In a specific embodiment, the liver cancer is hepatocellular carcinoma. The decrease in FGF19 levels can promote bile acid synthesis, and thus compounds that decrease FGF19 levels are useful for treating hyperlipidemia. In a specific embodiment, the invention provides an optical isomer shown in formula I or formula II or a hydrate, solvate, crystal or pharmaceutically acceptable salt thereof, a method for treating and/or preventing hyperlipidemia by using a compound shown in formula A or a hydrate, solvate, crystal or pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the compound and the hydrate, solvate, crystal or pharmaceutically acceptable salt thereof, and application of the compound in preparation of a medicine for treating and/or preventing hyperlipidemia.
In some embodiments, the present invention relates to a method for treating tumor, comprising administering to a patient in need thereof a therapeutically effective amount of an optical isomer represented by formula I or formula II or a hydrate, solvate, crystal or pharmaceutically acceptable salt thereof, a compound represented by formula a or a hydrate, solvate, crystal or pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same, wherein the tumor is selected from breast cancer, ovarian cancer, lung cancer, liver cancer, sarcoma, or the like.
Description of the terms
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
The optical isomers refer to substances with completely identical molecular structures, similar physical and chemical properties and different optical rotation. In the description of the optically active compounds, the prefixes D and L or R and S are used to designate the absolute configuration in relation to the chiral centre of the molecule. The prefixes (+) and (-) or d and l are used to specify the direction of rotation of the plane-polarized light by the compound. The compound is levorotatory as indicated by (-) or l. Compounds prefixed with (+) or d are dextrorotatory. Many organic compounds exist in an optically active form, i.e., they are capable of rotating the plane of plane polarized light. For a given chemical structure, different optically active compounds are called stereoisomers, which are identical except that they are mirror images of each other. A particular stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is referred to as an enantiomeric or racemic mixture.
In the present invention, a racemic mixture is "enriched" in a particular isomer when the particular isomer exceeds 50% of the composition of the mixture. By "substantially free" is meant that the compound includes less than about 10% of the undesired isomer, e.g., the amount of the undesired isomer may be less than 10%, e.g., 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or even less, as determined using conventional analytical methods routinely used by those skilled in the art. Isomer-enriched compounds containing about 95% or more of the desired isomer are referred to herein as "substantially pure" isomers. Isomer-enriched compounds containing about 99% or more of the desired isomer are referred to herein as "pure" stereoisomers. The purity of any isomer-enriched compound can be confirmed using conventional analytical methods.
The "pharmaceutical composition" of the present invention is intended to comprise a mixture of any one of the compounds described herein, including the corresponding isomers, prodrugs, solvates, pharmaceutically acceptable salts, or chemically protected forms thereof, and one or more pharmaceutically acceptable carriers. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to an organism. The compositions are generally useful for the preparation of medicaments for the treatment and/or prevention of diseases mediated by one or more kinases.
The "pharmaceutically acceptable carrier" of the present invention refers to a carrier that does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the administered compound, and includes all solvents, diluents or other excipients, dispersants, surfactant isotonicity agents, thickeners or emulsifiers, preservatives, solid binders, lubricants and the like. Unless any conventional carrier medium is incompatible with the compounds of the present invention. Some examples of carriers that may be pharmaceutically acceptable include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, and cellulose acetate; malt, gelatin, and the like.
"excipient" herein refers to an inert substance added to a pharmaceutical composition to further facilitate administration of the compound. Excipients may include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols.
The term "treating a tumor" as used herein refers to ameliorating a tumor, inhibiting the growth, development and/or metastasis of a cancer, or reducing the risk of developing a tumor, including cancers such as bladder, breast, kidney, liver, lung (including small cell lung), esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin (including squamous cell carcinoma), administering to a human or animal in need thereof a therapeutically and/or prophylactically effective amount of a compound of the invention to inhibit, slow or reverse the growth, development or spread of a tumor in a subject, ameliorate a tumor, or reduce the risk of developing a tumor; hematopoietic tumors of lymphoid lineage, including, for example, leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma and Burkitt's lymphoma; tumors of mesenchymal origin, including, for example, fibrosarcoma, rhabdomyosarcoma; hematopoietic tumors of myeloid lineage, including, for example, acute and chronic myelogenous leukemias, myelodysplastic syndrome, and promyelocytic leukemia; tumors of the central and peripheral nervous system, including, for example, astrocytomas, neuroblastomas, gliomas, and schwannomas; and other tumors, including, for example, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma, keratoacanthoma, thyroid follicular cancer, and kaposi's sarcoma.
The term "pharmaceutically acceptable salt" as used herein refers to pharmaceutically acceptable salts of the compounds of the present invention with acids which are safe and effective for use in a mammal and which have biological activity, such as, for example, inorganic acids such as phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid, organic acids such as citric acid, maleic acid, hydroxymaleic acid, propionic acid, glycolic acid, stearic acid, malonic acid, mandelic acid, succinic acid, fumaric acid, lactic acid, acetic acid, trifluoroacetic acid, glutamic acid, malic acid, tartaric acid, ascorbic acid, pamoic acid, benzoic acid, phenylacetic acid, glutamic acid, salicylic acid, oxalic acid, fumaric acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, hydroxyethanesulfonic acid, and the like.
The "hydrogen", "carbon" and "oxygen" in the compounds of the present invention include all isotopes thereof. Isotopes are understood to include those atoms having the same number of atoms but different mass numbers, e.g. isotopes of hydrogen including protium, tritium and deuterium, and isotopes of carbon including 12 C、 13 C and 14 c, isotopes of oxygen including 16 O and 18 o, and the like.
Detailed Description
The following representative examples are intended to better illustrate the present invention and are not intended to limit the scope of the present invention. The materials used in the following examples are all commercially available unless otherwise specified.
Example 1: preparation of N- (2- ((1R, 4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -5- (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1-ethyl-2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) -4-methoxyphenyl) but-2-ynylamide
Step 1: preparation of (1R, 4R) -5- (4-bromo-5-methoxy-2-nitrophenyl) -2-oxa-5-azabicyclo [2.2.1] heptane
1-bromo-4-fluoro-2-methoxy-5-nitrobenzene (176g, 0.70mol), (1R, 4R) -2-oxa-5-azabicyclo [2.2.1] was added to a 5000ml three-necked flask]Heptane hydrochloride (1) (105g, 0.77mol), potassium carbonate (291.9g, 2.11mol), 3000ml of N, N-dimethylformamide, and stirring at 100 ℃ for two hours. TLC (ethyl acetate: petroleum ether = 1) showed the reaction was complete. Washing with water, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, and concentrating to obtain yellow solid 215.3g, with yield: 92.83 percent. ESI-MS m/z:329.06 2[ 2 ], [ M + H ]] + .
Step 2: preparation of (1R, 4R) -5- (5-methoxy-2-nitro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -2-oxa-5-azabicyclo [2.2.1] heptane
(1R, 4R) -5- (4-bromo-5-methoxy-2-nitrophenyl) -2-oxa-5-azabicyclo [2.2.1] obtained in step 1]Heptane (71.45g, 0.22mol), pinacol diboron (166.0g, 0.65mol), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (15.9g, 0.022mol) and potassium acetate (64.0g, 0.65mol) were sequentially added to 1071mL1, 4-dioxane, and after replacement with argon, the mixture was reacted at 100 ℃ overnight. Filtering the reaction solution, spin-drying the filtrate, and performing column chromatography to obtain 59.1g of yellow solid, wherein the yield is as follows: 72.2 percent. ESI-MS m/z:377.22[ 2 ] M + H] + .
And step 3: preparation of 7- (4- ((1R, 4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -2-methoxy-5-nitrophenyl) -3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1-ethyl-1, 6-naphthyridin-2 (1H) -one
2-chloro-6- (2, 6-dichloro-3, 5-dimethoxyphenyl) -8-ethylpyrido [2,3-d ]]Pyrimidin-7 (8H) -one (170g, 0.41mol) was dissolved in 3400mL of 1, 4-dioxane and 850mL of water, and (1R, 4R) -5- (5-methoxy-2-nitro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -2-oxa-5-azabicyclo [ 2.2.1-yl ] phenyl]Heptane (170.6 g, 0.45mol), tetrakistriphenylphosphine-palladium (47.7g, 0.04mol), sodium carbonate (143.8g, 1.36mol), argon gas shield, and stirring at 100 ℃ for 2 hours, the reaction was complete. The mixture was cooled and left overnight, and filtered the next day to obtain a yellow solid, which was then dissolved in dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, slurried with ethyl acetate, and filtered to obtain 186.2g of a yellow solid with a yield of 72.1%. ESI-MS m/z of 627.26[ 2 ] M + H] + .
And 4, step 4: preparation of 7- (5-amino-4- ((1R, 4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -2-methoxyphenyl) -3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1-ethyl-1, 6-naphthyridin-2 (1H) -one
Reacting 7- (4- ((1R, 4R) -2-oxa-5-azabicyclo [ 2.2.1)]Hept-5-yl) -2-methoxy-5-nitrophenyl) -3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1-ethyl-1, 6-naphthyridin-2 (1H) -one (124.2g, 0.198mol) was dissolved in 2484mL of ethanol and 621mL of water, and iron powder (111.1g, 1.98mol) and ammonium chloride (105.1g, 1.98mol) were added and reacted at 100 ℃ under reflux for 2H. After the reaction is finished, the mixture is placed at room temperature for cooling, saturated sodium bicarbonate solution is added into the reaction solution for neutralization, then 2L dichloromethane is added for stirring for 10 minutes, the organic layer is dried by anhydrous sodium sulfate after filtration, ethyl acetate is added after concentration, pulping and filtration are carried out to obtain 117g of yellow solid, and the yield is high：99％。ESI-MS m/z:597.20[M+H] + .
And 5: preparation of 2-butynoyl chloride
2-Butynoic acid (100g, 1.20mol) is added into a 3000mL three-necked bottle, 1.98L of dichloromethane, 30mLN and N-dimethylformamide are added, stirring is carried out at-5 ℃ for 10min, then oxalyl chloride (151.2g, 1.20mol) is dropwise added, stirring is carried out at-5 ℃ for 20min, then, the mixture is transferred to room temperature for reaction for 1.5h for standby.
Step 6: preparation of N- (2- ((1R, 4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -5- (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1-ethyl-2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) -4-methoxyphenyl) but-2-ynylamide
7- (5-amino-4- ((1R, 4R) -2-oxa-5-azabicyclo [ 2.2.1)]Hept-5-yl) -2-methoxyphenyl) -3- (2, 6-dichloro-3-, 5-dimethoxyphenyl) -1-ethyl-1, 6-naphthyridin-2 (1H) -one (94.5 g, 0.158mol) is dissolved in 1600mL of dichloromethane, diisopropylethylamine (61.5 g,0.476 mol) is added, 400mL (0.6 mol/L,0.238 mol) of 2-alkynyl butyryl chloride is dropped while stirring at 5 ℃, the mixture is stirred for 15 minutes, 1L of saturated sodium bicarbonate aqueous solution is added, dichloromethane is used for extraction, organic phases are combined, drying and spinning-drying are carried out to obtain 125g of dark yellow solid, 750mL of tetrahydrofuran is added, the mixture is filtered after pulping, and a filter cake is washed by a small amount of ethyl acetate to obtain 84.9g of yellow solid, and the yield is 80.9%. ESI-MS m/z:663.33[ 2 ], [ M + H ]] + . 1 H-NMR(400MHz,DMSO-d 6 ):δ1.31(t,3H),1.88(s,2H),2.02(s,3H),3.05(d,1H),3.66(d,1H),3.80(d,1H),3.93(d,1H),3.95(s,3H),3.98(s,6H),4.30(q,2H),4.62(s,1H),4.66(s,1H),6.43(s,1H),7.01(s,1H),7.75(s,1H),7.98(s,1H),8.05(s,1H),8.91(s,1H),9.85(s,1H).
Example 2: preparation of N- (2- ((1S, 4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -5- (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1-ethyl-2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) -4-methoxyphenyl) but-2-ynylamide
The preparation method was the same as that of example 1, except that (1R, 4R) -2-oxa-5-azabicyclo [2.2.1] of step 1 of example 1 was used]Heptane hydrochloride was replaced by (1S,4S) -2-oxa-5-azabicyclo [2.2.1]]Heptane hydrochloride to yield the title compound. 1 H-NMR(400MHz,DMSO-d 6 ):δ1.30(t,3H),1.87(s,2H),2.02(s,3H),3.05(d,1H),3.65(d,1H),3.80(d,1H),3.92(d,1H),3.95(s,3H),3.97(s,6H),4.29(q,2H),4.61(s,1H),4.65(s,1H),6.42(s,1H),7.01(s,1H),7.74(s,1H),7.97(s,1H),8.04(s,1H),8.91(s,1H),9.85(s,1H).ESI-MS m/z:663.33[M+H] + .
Example 3: preparation of N- (2- (2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -5- (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1-ethyl-2-oxo-1, 2-dihydro-1, 6-naphthyridin-7-yl) -4-methoxyphenyl) but-2-ynylamide
The preparation method is the same as that of example 1 except that (1R, 4R) -2-oxa-5-azabicyclo [2.2.1] of step 1 of example 1]Replacement of Heptane hydrochloride by 2-oxa-5-azabicyclo [2.2.1]]Heptane hydrochloride to yield the title compound. 1 H-NMR(400MHz,DMSO-d 6 ):δ1.30(t,3H),1.87(s,2H),2.02(s,3H),3.05(d,1H),3.65(d,1H),3.80(d,1H),3.91(d,1H),3.95(s,3H),3.97(s,6H),4.30(q,2H),4.61(s,1H),4.65(s,1H),6.42(s,1H),7.01(s,1H),7.74(s,1H),7.97(s,1H),8.04(s,1H),8.91(s,1H),9.86(s,1H).ESI-MS m/z:663.2[M+H] + .
Comparative example 1 and comparative example 2
The compounds of comparative example 1 (compound a) and comparative example 2 (compound B) were prepared and identified by hydrogen spectroscopy and mass spectrometry according to the methods described in patent application WO2015/4108992 for compounds numbers 19 and 27.
Comparative example 3
The Compound is named N- ((3S, 4S) -3- ((6- (2, 6-dichoro-3, 5-dimethoxyphenyl) quinazolin-2-yl) amino) tetrahydrogen-2H-pyran-4-yl) acrylamide (BLU-554), prepared according to the synthetic method of Compound 40 in WO2015061572 and identified by hydrogen and mass spectrometry.
The inhibitory activity of compound a, compound B and compound C on FGFR4 kinase and FGFR1 kinase, the inhibitory activity on human hepatoma cell line Hep3B cells and HUH-7 cells, and the pharmacokinetic profile in mice were tested using the methods of experimental examples 1,2 and 3 below. The experimental results show that the selectivity of the compound A, the compound B and the compound C on FGFR4 kinase and FGFR1 kinase is obviously lower than that of the compound of the invention, the inhibitory activity on human liver cancer cell strains Hep3B cells and HUH-7 cells is obviously weaker than that of the compound of the invention, and the half-life and AUC are also inferior to that of the compound of the invention.
Experimental example 1 in vitro kinase Activity evaluation
1 materials of the experiment
FGFR1, purchased from Carna under catalog No. 08-133;
FGFR4, purchased from Carna under catalog No. 08-136;
p22 peptide, available from GL Biochem, catalog No. 112393;
staurosporine9, available from Sigma under catalog number S4400-1MG;
2 method of experiment
1) Preparation of 1 Xkinase base buffer and stop buffer
A.1 × kinase base buffer: 20mM HEPES, pH7.5, 0.01% Triton X-100, 10mM MgCl 2 ，2mM DTT。
B. Stop buffer: 100mM HEPES, pH7.5,0.015% Brij-35,0.2% coding reagent #3, 50mM EDTA.
2) Preparation of the Compounds
A. 10mM stock solutions of the compounds of the examples of the invention and reference compounds A, B and C were prepared.
B. Preparation of 50 × compound solution: the compounds of the above inventive examples and the reference compounds were diluted sequentially 3-fold in DMSO starting from 500 μ M for 10 concentrations.
C. 100 μ L of 100% DMSO was added to each of 2 empty wells of the same 96-well plate as no-compound and no-kinase controls. Label the 96-well plate as the source plate.
D. Preparing an intermediate plate: transfer 10 μ L of compound from source plate to a new 96-well plate as an intermediate plate; add 90. Mu.L of 1 Xkinase buffer to each well of the intermediate plate; shaking and mixing for 10min.
3) Preparing an experimental plate: transfer 5 μ L per well from 96 well intermediate plates to 384 well plates, 2 wells.
4) Kinase reaction
A. Preparation of 2.5 × kinase solution: the kinases were added separately to 1 × base buffer.
B. Preparation of 2.5 × polypeptide solution: FAM-labeled polypeptide and ATP were added to 1 × base buffer.
C. The assay plates already contained 5. Mu.L of compound (10% DMSO).
D. Transfer 2.5 × kinase solution to assay plate: add 10. Mu.L of 2.5 Xkinase solution to each well of a 384 well assay plate.
E. Incubate at room temperature for 10min.
F. Transfer 2.5 × polypeptide solution to assay plate: add 10. Mu.L of 2.5 Xpolypeptide solution to each well of a 384 well assay plate.
G. Kinase reaction and termination: incubating at 28 ℃ for a certain period of time; the reaction was stopped by adding 25. Mu.L of stop buffer.
5) Caliper instrument reading: data were read on the Caliper instrument.
6) Fitting curve
A. Translation value data is obtained from the Caliper program.
B. The conversion value was converted into the inhibition rate.
Inhibition% = (maximum conversion value-actual conversion value)/(maximum conversion value-minimum conversion value) × 100, where "maximum conversion value" represents DMSO vehicle control with or without kinase compound and "minimum conversion value" represents no kinase compound control.
C. Computing IC by using Xlfit excel add-in 4.3.1 data processing software 50 The value is obtained. Calculating the formula: y = Bottom + (Top-Bottom)/(1 + LogIC) 50 /X). Times.HillSlope) and the results are shown in Table 1:
TABLE 1
| FGFR4 kinase IC 50 (nM) | FGFR1 kinase IC 50 (nM) | |
| Compound A | 34 | 200 |
| Compound B | 85 | - |
| Compound C | 13 | 653 |
| Example 1 | 5.4 | 3069 |
| Example 2 | 4.6 | 2226 |
"-" indicates not measured
Experimental results show that the compound has strong inhibitory activity on FGFR4 kinase, low inhibitory activity on FGFR1 kinase and obviously better selectivity on FGFR4 kinase and FGFR1 kinase than a reference compound. Therefore, the compounds of the present invention are kinase inhibitors with active advantages selective for FGFR4, useful for the treatment of FGFR4 kinase-associated diseases, and may reduce side effects caused by inhibition of FGFR1 kinase.
Experimental example 2 cell proliferation inhibition experiment
1 materials of the experiment
1.1 Compounds: the experiment was carried out using the compounds of the examples of the present invention, compound a, compound C.
1.2 cells: hep3B cells and HUH-7 cells were provided by Shanghai Mingkude New drug development Co., ltd.
1.3 reagent: FBS, DMEM, media purchased from GIBCO;
CellTiter Glo, available from Promega.
1.4 instrument Tecan D300e quick pipettor; biotek fluorescence detector
2 Experimental methods
All compounds were dissolved in DMSO and stored in a-20 ℃ freezer.
Day-1: according to 3X10 3 Density of individual cells/well cells were added to 96 wells at 100. Mu.l per well;
blank control was added to 100. Mu.l of medium per well; add 100. Mu.l PBS to the remaining untested edge wells;
day 0: setting a compound loading program, and automatically loading by using Tecan D300 e;
the initial concentration of test compound was 10 μ M,3 fold dilution, 9 concentration, replicate wells;
the initial concentration of positive reference Staurosporine is 1 mu M,3 times of dilution, 9 concentrations and multiple wells;
day 3. Equilibrate the experimental 96-well plate for 30 minutes at room temperature;
compound solubility and cell status were observed prior to addition of CTG;
50 μ l CellTiter Glo reagent was added to each well and signals were detected after 10 minutes using BioTec (Luminescence).
3, data analysis:
XL-fit software analysis data (supplier: ID Business Solution Ltd., version: XL fit 5.0)
Calculating the formula: r (%) = {1-RLU Compound (I) -RLU Blank space }/{RLU Control -RLU Blank space } × 100%, results are shown in table 2:
TABLE 2
| Compound number | Hep3B cell Rel _ IC 50 (nM) | HUH-7 cells Rel _ EC 50 (nM) |
| Compound A | - | 230 |
| Compound C | 40 | 140 |
| Example 1 | 36 | 51 |
| Example 2 | 13 | - |
"-" indicates not measured
Experimental results show that the compound has very good inhibitory activity on proliferation of human hepatoma cell strains HePB and HuH-7 cells amplified by FGFR4 DNA, the activity of part of the compound is far superior to that of a reference compound, and the compound is an effective FGFR4 selective inhibitor.
Experimental example 3 drug metabolism experiment
1 test materials
1.1 Compounds
The experiment was performed using the compounds of the examples of the invention and the reference compounds a, B and C. The oral drug formulation is 10% ethanol, 10% solutol,80% normal saline dissolved to make 0.5mg/ml clear solution, the intravenous drug formulation is 2% ethanol, 2% solutol,96% normal saline dissolved to make 0.1mg/ml clear solution.
1.2 animals
Male BALB/c mice, 3 each per group, weight 18-22, supplied by Shanghai Sphere-BiKai laboratory animals Co., ltd. The test mice are given an environmental adaptation period of 2-4 days before the experiment, fasted for 8-12h before the administration, fed with water after 2h and fed with food after 4 h.
1.3 reagents
Methanol (chromatographically pure): manufactured by Spectrum corporation; acetonitrile (chromatographically pure): manufactured by Spectrum corporation; the other reagents were all commercially available analytical grade.
1.4 instruments
API 4500 model triple quadrupole LC MS, available from AB corporation, USA, equipped with electrospray ionization source (ESI), LC-30AD dual pump; SIL-30AC autosampler; a CTO-30AC column incubator; a DGU-20A3R degasser; an Analyst QSA01.01 chromatography workstation; milli-Q ultra-pure water devices (Millipore Inc); a Qilinbeier Vortex-5 oscillator; HITACHI CF16 RXII bench-top high speed refrigerated centrifuge.
2 method of experiment
1) After the mice are fasted but can drink water freely for 12 hours, blank plasma at 0 moment is adopted;
2) Taking 3 mice in step 1), intragastric administration (i.g.) of 10mg/kg of the compound of the present example and the reference compound; intravenous (i.v.) administration of the compounds of the examples of the invention and the reference compound at 1mg/kg;
3) Continuously taking blood from fundus venous plexus after intragastric administration for 5min,15min,30min,1h,2h,4h,8h,10h and 24h, placing the blood into an EP tube distributed with heparin, centrifuging at 8000rpm/min for 5min, taking upper layer plasma, freezing and storing at-20 ℃, and analyzing by LC-MS/MS;
4) Calculating pharmacokinetic parameters by using WinNonlin software according to the blood concentration-time data obtained in the step 3), and the results are shown in Table 3.
TABLE 3
"-" indicates not measured
Experiments show that the oral absorption exposure of mice to the compound of the invention is obviously higher than that of a reference compound, and the half life is longer than that of the reference compound, so that the compound can be ensured to have longer effective blood concentration in the mice.
Example 4: hERG
1: preparation of solutions and compounds:
extracellular fluid (mM): N-2-hydroxythiolpiperazine-N' -2-ethanesulfoformic acid (HEPES) 10, naCl 145, KCl 4, caCl22, mgCl21, glucose 10, and adjusting the pH to 7.4 with 1N sodium hydroxide; adjusting osmotic pressure to 290-300mOsm; filtered and stored at 4 ℃.
Electrode internal solution (in mM): KCl 120, KOH 31.25, caCl25.374, mgCl21.75, ethylene glycol-bis (β -aminoethylene ether) -N, N, N ', N' -tetraacetic acid (EGTA) 10, HEPES 10, na2-ATP 4, pH adjusted to 7.2 with 1N potassium hydroxide; adjusting osmotic pressure to 280-290mOsm; filtering, and storing at-20 deg.C.
2: preparation of the compound: the positive control drugs amitriptyline hydrochloride and SHC0192331 were first dissolved in 100% DMSO (Sigma-Aldrich, D2650) in stock solutions of 30 and 10mM, respectively. The stock solutions were diluted 1000-fold or 333-fold with DMSO to the respective assay concentrations before the assay, and then diluted 1000-fold or 333-fold with extracellular fluid to the desired concentration. The final concentration of DMSO in the extracellular fluid was 0.10% or 0.3%.
3: cell line
The stable cell line CHO-hERG was purchased from AVIVA. The hERG current was recorded on this cell line. For quality control, the minimum blocking resistance is not less than 500M Ω, and the hERG current is not less than 0.4nA.
4: electrophysiological test
Whole cell patch clamp technology was used to record hERG currents. The cell suspension was taken, added to a 35mm petri dish and placed on the stage of an inverted microscope. After the cells adhere to the wall, the cells are perfused by extracellular fluid with the flow rate of 1-2mL/min. The glass microelectrode is drawn by a microelectrode drawing instrument in two steps, and the water inlet resistance value of the glass microelectrode is 2-5M omega. After whole cell recording was established, the clamp potential was maintained at-80 mV. Depolarization to +60mV when given voltage stimulation, and then repolarization to-50 mV elicits hERG tail current. All recordings were made after the current had stabilized. The extracellular perfusion administration is started from low concentration, each concentration is 5-10min until the current is stable, and then the next concentration is given.
5: data collection and analysis
Stimulation emission and signal acquisition are carried out through Digidata 1440 (Molecular Devices) and pCLAMP software (version 10.2, molecular Devices) A/D-D/A digital-to-analog conversion; the signals were amplified by a patch clamp amplifier (multiclad 700b, molecular Devices).
Further data analysis and curve fitting were performed using claupfit (version 10.2, molecular Devices), EXCEL (version 2013, microsoft) and GraphPad Prism. Data are presented as mean ± standard deviation.
In data processing, when the blocking effect on hERG is judged, tail electricity is usedThe peak of the flow and its baseline are corrected. The effect of each compound at different concentrations is expressed as the inhibition of the wake. IC (integrated circuit) 50 The values were fitted by the Hill equation:
y: I/Icontrol; max: is 100%; min: is 0%; [ drug]: the concentration of the test substance; nH: a Hill slope; IC (integrated circuit) 50 : the maximum half inhibitory concentration of the test substance.
TABLE 4
| Compound number | hERG(nM) |
| Compound C | 3.85 |
| Example 1 | >30 |
| Example 2 | >30 |
The experimental results show that the examples 1 and 2 of the invention have no obvious inhibition effect on hERG, and the risk is lower than that of the compound C.
Example 5: liver distribution in mice
1 test materials
1.1 Compounds
The experiment was carried out using the compounds of the examples of the invention and the reference compound C. The oral pharmaceutical formulation was 10% ethanol, 20% PG, dissolved in 70% pure water, the example compound was made into a3,10,20mg/ml clear solution, and compound C was made into a 3mg/ml clear solution.
1.2 animals
Male BALB/c mice, 6 each per group, weighing 18-22, were provided by Shanghai Spire-BikKa laboratory animals, inc. The test mice were given an environmental acclimation period of 2-4 days prior to the experiment.
1.3 reagent
Methanol (chromatographically pure): manufactured by Spectrum corporation; acetonitrile (chromatographically pure): manufactured by Spectrum corporation; the other reagents were all commercially available analytical grade.
1.4 Instrument
API 4500 model triple quadrupole LC MS, manufactured by American AB corporation, equipped with electrospray ionization (ESI), LC-30AD dual pump; SIL-30AC autosampler; a CTO-30AC column incubator; a DGU-20A3R degasser; an Analyst QSA01.01 chromatography workstation; milli-Q ultra pure water devices (Millipore Inc); a Qilinbeier Vortex-5 oscillator; HITACHI CF16 RXII bench-top high speed refrigerated centrifuge.
2 method of experiment
1) Each group of 6 mice was intragastrically administered (i.g.) with 30, 100, 200mg/kg of the compound of the present example and 30mg/kg of the reference compound twice a day for 7 consecutive days.
2) 2h after the intragastric administration on the 7 th day, continuously taking blood from the fundus venous plexus, placing the blood into an EP tube distributed with heparin, centrifuging the blood for 5min at 8000rpm/min, taking upper plasma, freezing and storing the upper plasma at the temperature of minus 20 ℃, and analyzing the upper plasma by LC-MS/MS;
3) At 2h after gavage on day 7, the mice were dissected, livers were taken, homogenates were weighed, frozen at-20 ℃ and stored for LC-MS/MS analysis.
4) LC-MS/MS analysis analyzed compound concentrations in blood and liver.
The results are shown in Table 5:
table 5 mouse liver distribution data
"-" indicates not measured
The experimental results show that the concentration of the compound of example 1 in the liver of the target tissue is the highest, and the concentration of the compound of example 1 and the compound of example 2 in the liver of the target tissue is better than that of the compound C when the dosage is 30 mg/kg. In addition, the hepato-hematologic ratios of the compound of example 1 were higher than that of the compound of example 2 in all of the 3 doses of 30mg/kg, 100mg/kg, and 200 mg/kg.
Although the present invention has been described in detail above, those skilled in the art will appreciate that various modifications and changes can be made to the present invention without departing from the spirit and scope of the invention. The scope of the invention is not to be limited by the above detailed description but is only limited by the claims.
Claims (4)
1. A method for preparing an optical isomer represented by formula I or formula II or a pharmaceutically acceptable salt thereof, comprising:
(1) Reacting a compound of formula i with a compound of formula ii or a salt thereof under basic conditions to produce a compound of formula iii;
(2) The compound of the formula iii is reacted under conventional reaction conditions to produce the compound of the formula iv;
(3) Reacting the compound shown in the formula iv with the compound shown in the formula v through palladium mediated coupling reaction to obtain a compound shown in the formula vi;
(4) Reducing the nitro group on the compound of the formula vi into amino group through reduction reaction to obtain a compound of a formula vii;
(5) Reacting the compound of formula vii with a compound of formula viii by amide coupling to obtain a compound of formula viii;
wherein the dotted line
Is shown as
LG 1 、LG 2 Represents a leaving group;
m is-B (OR) 1 ) 2 -Sn (alkyl) or-Zn-halo-, wherein R 1 Is H or methyl;
x is halogen.
2. The process for preparing a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein the leaving groups are the same or different and are each independently a halogen or a sulfonyloxy group.
3. The process for preparing a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein the leaving groups are the same or different and are each independently Cl, br, I.
4. A process for preparing a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, as claimed in claim 1 wherein X is bromo.
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