WO2017211248A1 - 一种取代的咪唑并喹唑啉化合物及其药物组合物 - Google Patents

一种取代的咪唑并喹唑啉化合物及其药物组合物 Download PDF

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WO2017211248A1
WO2017211248A1 PCT/CN2017/087140 CN2017087140W WO2017211248A1 WO 2017211248 A1 WO2017211248 A1 WO 2017211248A1 CN 2017087140 W CN2017087140 W CN 2017087140W WO 2017211248 A1 WO2017211248 A1 WO 2017211248A1
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compound
imidazoquinazoline
hydrogen
compound according
disease
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PCT/CN2017/087140
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English (en)
French (fr)
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王义汉
李焕银
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深圳市塔吉瑞生物医药有限公司
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Priority to CN201780004831.8A priority Critical patent/CN108368117B/zh
Publication of WO2017211248A1 publication Critical patent/WO2017211248A1/zh

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    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention belongs to the technical field of medicine, and in particular relates to an imidazoquinazoline compound and a composition comprising the same and use thereof.
  • Phosphatidylinositol 3-kinases are a class of phospholipids that specifically catalyze the hydroxy group at the 3 position of Phosphatidylinositol (PI) and its derivatives and produce a second messenger
  • PI3Ks-mediated signaling is involved in the regulation of various cell functions such as cell division, differentiation, apoptosis, metabolism, and angiogenesis, and plays an important role in the activation of various cellular biological functions.
  • Type I PI3K phosphorylates phosphatidylinositol, phosphatidylinositol-4-phosphate and phosphatidylinositol-4,5-bisphosphate to produce phosphatidylinositol-3-phosphate and phosphatidyl Alcohol-3,4-diphosphate and phosphatidylinositol-3,4,5-triphosphate.
  • Type II PI3K phosphorylates PI and phosphatidylinositol-4-phosphate, while type III PI3K only phosphorylates PI.
  • PI3K phosphatidylinositol-3-kinase
  • the present invention discloses an imidazoquinazoline compound, a composition comprising the same, and use thereof, which have phosphatidylinositol 3-kinase (PI3K) inhibitory activity and have better pharmacological effects Learning / pharmacokinetic properties.
  • PI3K phosphatidylinositol 3-kinase
  • a phosphatidylinositol 3-kinase (PI3K) inhibitor such as an imidazoquinazoline compound of the formula (I), or a crystalline form thereof, a pharmaceutically acceptable salt, a hydrate or a solvent compound,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 and R 25 are each independently hydrogen, deuterium or halogen;
  • the imidazoquinazoline compound contains at least one ruthenium atom.
  • the cerium isotope content of cerium in the deuterated position is at least 0.015%, preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably greater than the natural strontium isotope content. More than 95%, more preferably more than 99%.
  • the strontium isotope content of strontium at each metamorphic position is at least greater than the natural strontium isotope content (0.015%), preferably greater than 30%, more preferably greater than 50%, and even more preferably greater than 75%. More preferably greater than 95%, more preferably greater than 99%.
  • the cesium isotope content of each of the R 5 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 and R 25 is at least 5%, preferably greater than 10 More preferably, more than 15%, more preferably more than 20%, more preferably more than 25%, more preferably more than 30%, more preferably more than 35%, more preferably more than 40%, more preferably more than 45% More preferably greater than 50%, more preferably greater than 55%, more preferably greater than 60%, more preferably greater than 65%, more preferably greater than 70%, more preferably greater than 75%, and even more preferably greater than 80%, More preferably greater than 85%, more preferably greater than 90%, more preferably greater than 95%
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrazine or hydrogen.
  • R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are each independently hydrazine or hydrogen.
  • R 15 and R 16 are each independently hydrazine or hydrogen.
  • R 17 , R 18 and R 19 are each independently hydrazine or hydrogen.
  • R 20 , R 21 , R 22 and R 23 are each independently hydrazine or hydrogen.
  • R 24 and R 25 are each independently hydrazine or hydrogen.
  • the imidazoquinazoline compound may be selected from any of the following structures, or a pharmaceutically acceptable salt thereof:
  • the compound does not include a non-deuterated compound.
  • the present invention also discloses a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an imidazoquinazoline compound as described above, or a crystalline form, a pharmaceutically acceptable salt, hydrate or solvate thereof.
  • the invention also relates to pharmaceutical compositions comprising one or more compounds of the invention. These pharmaceutical compositions can be used to achieve the desired pharmaceutical effect by administering them to a patient in need thereof.
  • Patient refers to a mammal, including a human, in need of treatment for a particular condition or disorder.
  • the invention includes a pharmaceutical composition consisting of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of the invention or a salt thereof.
  • the pharmaceutically acceptable carrier is preferably a relatively non-toxic carrier and is not deleterious to the patient at a concentration consistent with the effective activity of the active ingredient, such that any side effects of the carrier are not detracting from the utility of the active ingredient.
  • the pharmaceutically effective amount of the compound is preferably an amount that produces an effect or exerts an effect on the particular condition being treated.
  • the compounds of the present invention can be administered with well-known pharmaceutically acceptable carriers, in any effective conventional unit dosage form, including immediate, slow and timed release formulations, including oral, parenteral, topical, Intranasal administration, ocular administration, sublingual administration, rectal administration, vaginal administration, and the like.
  • the compound can be formulated into a solid or liquid preparation, such as a capsule, a pill, a tablet, a lozenge, a lozenge, a melt, a powder, a solution, a suspension or an emulsion, and may be A method of producing a pharmaceutical composition is known.
  • the solid unit dosage form can be a conventional hard or soft shell gelatin capsule type containing, for example, a surfactant, a lubricant, and an inert filler such as lactose, sucrose, calcium phosphate, and corn starch.
  • the compound of the present invention and a conventional tablet base such as lactose, sucrose, and corn starch may be tableted by combining the following ingredients: a binder such as gum arabic, corn starch or gelatin; a disintegrant (using To help break down and dissolve tablets after administration, such as potato starch, alginic acid, corn starch and guar gum, tragacanth and gum arabic; lubricants (to improve tablet granulation fluidity and prevent a tablet material adhered to the surface of the tablet mold and the die hole, such as talc, stearic acid, or magnesium stearate, calcium stearate or zinc stearate; a dye; a colorant; and a flavoring agent (for Improve the sensory quality of tablets and make them more acceptable to patients, such as peppermint, wintergreen oil or cherry flavoring.
  • a binder such as gum arabic, corn starch or gelatin
  • a disintegrant using To help break down and dissolve tablets after administration, such as potato starch, al
  • Suitable excipients for oral liquid dosage forms include: dicalcium phosphate and diluent
  • dicalcium phosphate and diluent For example, water and alcohols, for example, ethanol, benzyl alcohol and polyethylene glycol, with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifier.
  • Various other materials can be used as a coating or to modify the physical form of the formulation unit. For example, tablets, pills or capsules may be coated with shellac, sugar or both.
  • Dispersible powders and granules are suitable for formulation into aqueous suspensions. They contain the active ingredient, dispersing or wetting agents, suspending agents and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are listed above by way of example. Other excipients, such as the sweeteners, flavoring agents, and coloring agents described above, may also be included.
  • the pharmaceutical composition of the present invention may also employ an oil-in-water emulsion.
  • the oil phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils.
  • Suitable emulsifiers may be: natural gums such as gum arabic and tragacanth; phospholipids such as soybeans and lecithin present in nature; esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono-oil An acid ester; a condensation product of the above partial ester with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweeteners and flavoring agents.
  • the pharmaceutical composition may also be in the form of a sterile injectable aqueous suspension.
  • suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents.
  • suspending agents are, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, tragacanth and gum arabic.
  • the dispersing or wetting agent may be a phospholipid present in nature, such as lecithin, a condensation product of an alkylene oxide with a fatty acid (such as polyoxyethylene stearate), a condensation product of ethylene oxide with a long-chain fatty alcohol (such as heptaacetate).
  • Cetyl alcohol condensation products of ethylene oxide with partial esters (derived from fatty acids and hexitols) (such as polyoxyethylene sorbitan monooleate), or ethylene oxide and partial esters (derived from fatty acids and hexitols) a condensation product (such as polyoxyethylene sorbitan monooleate).
  • partial esters derived from fatty acids and hexitols
  • ethylene oxide and partial esters derived from fatty acids and hexitols
  • a condensation product such as polyoxyethylene sorbitan monooleate
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • Diluents and solvents which may be used are, for example, water, Ringer's solution, isotonic sodium chloride solution and isotonic glucose solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspension medium.
  • any non-irritating, non-volatile oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the formulation of injectables.
  • compositions of the invention may also be administered in a suppository form suitable for rectal administration.
  • These compositions are formulated by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures and liquid at the temperature of the rectum, and thus melts in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures and liquid at the temperature of the rectum, and thus melts in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures and liquid at the temperature of the rectum, and thus melts in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycol.
  • transdermal delivery device Another dosage form for use in the methods of the invention is the use of a transdermal delivery device.
  • a transdermal patch can be used to continuously or intermittently infuse a compound of the invention in a controlled amount.
  • the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art (U.S. Patent No. 5,023,252).
  • the patch can be constructed to deliver the agent continuously, pulsed, or as needed.
  • Controlled release dosage forms for parenteral administration include known liposomal agents, polymeric microspheres, and polymeric gels.
  • a mechanical delivery device for delivering a medicament Structures and usage are well known in the art.
  • Direct techniques such as direct application to the brain, typically require insertion of a drug delivery catheter into the patient's ventricular system to avoid the blood-brain barrier.
  • One such implantable delivery system for delivering a medicament to a particular body anatomical region is described in U.S. Patent No. 5,011,472.
  • the invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein.
  • isotopes which may be listed as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, respectively. , 31 P, 32 P, 35 S, 18 F and 36 Cl. a compound, or an enantiomer, a diastereomer, an isomer, or a pharmaceutically acceptable salt or solvate of the present invention, wherein an isotope or other isotopic atom containing the above compound is within the scope of the present invention .
  • isotopically-labeled compounds of the present invention such as the radioisotopes of 3 H and 14 C, are also among them, useful in tissue distribution experiments of drugs and substrates. ⁇ , ie 3 H and carbon-14, ie 14 C, are easier to prepare and detect and are preferred in isotopes. In addition, heavier isotopic substitutions such as guanidine, or 2 H, are preferred in certain therapies due to their good metabolic stability, such as increased half-life or reduced dosage in vivo, and therefore may be preferred in certain circumstances. Isotopically labeled compounds can be prepared in a conventional manner by substituting a readily available isotopically labeled reagent with a non-isotopic reagent using the protocol of the examples.
  • the present invention also discloses the use of an imidazoquinazoline compound as described above for the preparation of a pharmaceutical composition for a disease associated with phosphatidylinositol 3-kinase (PI3K).
  • PI3K phosphatidylinositol 3-kinase
  • it is used for the preparation of a medicament for inhibiting phosphatidylinositol 3-kinase (PI3K) mediated diseases, such as cancer, cell proliferative diseases, angiogenic diseases, inflammatory diseases, autoimmune diseases, cardiovascular diseases, nerves Degenerative diseases, metabolic disorders, nociceptive diseases, eye diseases, lung diseases or kidney diseases.
  • the cell proliferative diseases of the present invention include, but are not limited to, psoriasis, keloids and other hyperplasia affecting the skin, benign prostatic hyperplasia (BPH), solid tumors (such as breast cancer, respiratory cancer, brain cancer, genital cancer). , digestive tract cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer and their distant metastasis), as well as lymphoma, sarcoma and leukemia.
  • BPH benign prostatic hyperplasia
  • solid tumors such as breast cancer, respiratory cancer, brain cancer, genital cancer
  • digestive tract cancer urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer and their distant metastasis
  • lymphoma sarcoma and leukemia.
  • the imidazoquinazoline compound of the present invention has excellent inhibitory properties against phosphatidylinositol 3-kinase (PI3K).
  • PI3K phosphatidylinositol 3-kinase
  • the technique of deuteration is used to alter the metabolism of a compound in an organism, giving the compound better pharmacokinetic parameter characteristics. In this case, the dosage can be changed and a long-acting preparation can be formed to improve the applicability.
  • replacing the hydrogen atom in the compound with hydrazine can increase the drug concentration of the compound in the animal due to its strontium isotope effect, thereby improving the efficacy of the drug.
  • replacing the hydrogen atom in the compound with hydrazine can inhibit certain metabolites and improve the safety of the compound.
  • Triethylamine (Et 3 N, 8 mL) and acetic anhydride (Ac 2 O, 4 mL, 42.34 mmol) were added dropwise to a stirred solution of compound 4 (4.38 g, 28.23 mmol) in dichloromethane (100 mL) Stir at room temperature for 1 hour. After the reaction of the reaction substrate was completed, 30 mL of water was added, and the mixture was extracted with methylene chloride. The organic phase was collected and purified by column to give Compound 5 as a white solid, a total of 3.5 g, yield 63%.
  • the kinase activity of the compounds of the invention was tested according to the methods described in the literature J. Med. Chem. 2013, 56, 1922-1939.
  • the experimental results show that the compounds of the examples of the present invention showed deliberate inhibitory activity against phosphatidylinositol 3-kinase (PI3K) with an IC 50 ⁇ 20 nM.
  • PI3K phosphatidylinositol 3-kinase
  • Microsomal experiments human liver microsomes: 0.5 mg/mL, Xenotech; rat liver microsomes: 0.5 mg/mL, Xenotech; coenzyme (NADPH/NADH): 1 mM, Sigma Life Science; magnesium chloride: 5 mM, 100 mM phosphate buffer Agent (pH 7.4).
  • Preparation of stock solution Weigh a certain amount of compound powder and dissolve it to 5 mM with DMSO.
  • phosphate buffer 100 mM, pH 7.4.
  • the pH was adjusted to 7.4, diluted 5 times with ultrapure water before use, and magnesium chloride was added to obtain a phosphate buffer (100 mM) containing 100 mM potassium phosphate, 3.3 mM magnesium chloride, and a pH of 7.4.
  • NADPH regeneration system containing 6.5 mM NADP, 16.5 mM G-6-P, 3 U/mL G-6-P D, 3.3 mM magnesium chloride was prepared and placed on wet ice before use.
  • Formulation stop solution acetonitrile solution containing 50 ng/mL propranolol hydrochloride and 200 ng/mL tolbutamide (internal standard). Take 25057.5 ⁇ L of phosphate buffer (pH 7.4) into a 50 mL centrifuge tube, add 812.5 ⁇ L of human liver microsomes, and mix to obtain a liver microsome dilution with a protein concentration of 0.625 mg/mL. 25057.5 ⁇ L of phosphate buffer (pH 7.4) was taken into a 50 mL centrifuge tube, and 812.5 ⁇ L of SD rat liver microsomes were added and mixed to obtain a liver microsome dilution having a protein concentration of 0.625 mg/mL.
  • the corresponding compound had a reaction concentration of 1 ⁇ M and a protein concentration of 0.5 mg/mL.
  • 100 ⁇ L of the reaction solution was taken at 10, 30, and 90 min, respectively, and added to the stopper, and the reaction was terminated by vortexing for 3 min.
  • the plate was centrifuged at 5000 x g for 10 min at 4 °C.
  • 100 ⁇ L of the supernatant was taken into a 96-well plate to which 100 ⁇ L of distilled water was previously added, mixed, and sample analysis was performed by LC-MS/MS.
  • the metabolic stability of human and rat liver microsomes was evaluated by simultaneously testing the compounds of the present invention and their compounds without deuteration.
  • the half-life and liver intrinsic clearance as indicators of metabolic stability are shown in Table 1.
  • the undeuterated compound Copanlisib (2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[ 1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide) was used as a control sample.
  • the compounds of the present invention can significantly improve metabolic stability by comparison with the undeuterated compound Copanlisib.
  • SD rat grade SPF grade
  • Weight range 180 ⁇ 220g (actual weight range is 187 ⁇ 197g)
  • the male SD rats were subjected to ig-administered RVT-101 (3 mg/kg) and the compound of the example (3 mg/) according to the non-compartmental statistical moment theory using Winnonin software. Pharmacokinetic related parameters after kg).
  • the compound of the present invention has superior activity and has excellent pharmacokinetic properties, and thus is more suitable as a compound which inhibits phosphatidylinositol 3-kinase.

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Abstract

本发明公开了如式（I）所示的取代的咪唑并喹唑啉化合物以及含有该化合物、或其晶型、药学上可接受的盐、前药、立体异构体、同位素变体、水合物或溶剂合物的药物组合物及其用途。本发明公开的咪唑并喹唑啉化合物及包含该化合物的组合物可用于治疗和/或预防磷脂酰肌醇3-激酶(PI3K)相关性疾病，例如癌症、细胞增殖性疾病等。

Description

一种取代的咪唑并喹唑啉化合物及其药物组合物 技术领域
本发明属于医药技术领域，尤其涉及一种咪唑并喹唑啉化合物及包含该化合物的组合物及其用途。
背景技术
磷脂酰肌醇-3-激酶(Phosphatidylinositol 3-kinases，PI3Ks)是一类特异性催化磷脂酰肌醇(Phosphatidylinositol，PI)及其衍生物的3位羟基磷酸化并产生具有第二信使作用的磷脂酰肌醇-3-磷酸(Phosphatidylinositol-3,4,5-triphosphate，PI3P)的酶。PI3Ks介导的信号传导参与细胞分裂、分化、凋亡、代谢以及血管生成等多种细胞功能的调节，对多种细胞生物功能的活化起到重要作用。近年来研究表明，PI3Ks和下游分子蛋白激酶B(Protein Kinase B，PKB或Akt)所组成的信号通路与肿瘤的发生、发展密切相关，调节肿瘤细胞的增殖、凋亡，促进肿瘤血管形成等。
目前，基于底物的特异性将PI3-激酶酶家族分为三类。I型PI3K能够使磷脂酰肌醇、磷脂酰肌醇-4-磷酸酯和磷脂酰肌醇-4,5-二磷酸酯磷酸化，分别产生磷脂酰肌醇-3-磷酸酯、磷脂酰肌醇-3,4-二磷酸酯和磷脂酰肌醇-3,4,5-三磷酸酯。II型PI3K使PI和磷脂酰肌醇-4-磷酸酯磷酸化，而III型PI3K仅使PI磷酸化。
虽然磷脂酰肌醇-3-激酶(PI3K)是抗肿瘤新药研发的重要靶点之一，然而除了雷帕霉素(rapamycin)及同系物以外，抑制PI3K信号传导通路的研究进展相对缓慢，特别是特异性抑制PI3K亚型(如I型PI3K包括p110α，p110β，p110δ等)的抑制剂的开发还具有很大的挑战性。
因此，本领域仍需要开发对磷脂酰肌醇3-激酶(PI3K)有抑制活性或更好药效学性能的化合物。
发明内容
针对以上技术问题，本发明公开了一种咪唑并喹唑啉化合物及包含该化合物的组合物及其用途，其具有磷脂酰肌醇3-激酶(PI3K)抑制活性，且具有更好的药效学/药代动力学性能。
对此，本发明采用的技术方案为：
一种磷脂酰肌醇3-激酶(PI3K)抑制剂，如式(I)所示的咪唑并喹唑啉化合物，或其晶型、药学上可接受的盐、水合物或溶剂化合物，
Figure PCTCN2017087140-appb-000001
其中，R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23、R24和R25各自独立地为氢、氘或卤素；
附加条件是，所述咪唑并喹唑啉化合物至少含有一个氘原子。
作为本发明的进一步改进，氘在氘代位置的氘同位素含量至少是大于天然氘同位素含量0.015％，较佳地大于30％，更佳地大于50％，更佳地大于75％，更佳地大于95％，更佳地大于99％。
在另一优选例中，氘在各氘代位置的氘同位素含量至少是大于天然氘同位素含量(0.015％)，较佳地大于30％，更佳地大于50％，更佳地大于75％，更佳地大于95％，更佳地大于99％。
具体地说，在本发明中R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23、R24和R25各氘代位置中氘同位素含量至少是5％，较佳地大于10％，更佳地大于15％，更佳地大于20％，更佳地大于25％，更佳地大于30％，更佳地大于35％，更佳地大于40％，更佳地大于45％，更佳地大于50％，更佳地大于55％，更佳地大于60％，更佳地大于65％，更佳地大于70％，更佳地大于75％，更佳地大于80％，更佳地大于85％，更佳地大于90％，更佳地大于95％，更佳地大于99％。
在另一选例中，式(I)中化合物的R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23、R24和R25，至少其中一个R含氘，更佳地两个R含氘，更佳地三个R含氘，更佳地四个R含氘，更佳地五个R含氘，更佳地六个R含氘，更佳地七个R含氘，更佳地八个R含氘，更佳地九个R含氘，更佳地十个R含氘，更佳地十一个R含氘，更佳地十二个R含氘，更佳地十三个R含氘，更佳地十四个R含氘，更佳地十五个R含氘，更佳地十六个R含氘，更佳地十七个R含氘，更佳地十八个R含氘，更佳地十九个R含氘，更佳地二十个R含氘，更佳地二十一个R含氘，更佳地二十二个R含氘，更佳地二十三个R含氘，更佳地二十四个R含氘，更佳地二十五个R含氘。
作为本发明的进一步改进，R1、R2、R3、R4、R5、R6、R7和R8各自独立地为氘或氢。
作为本发明的进一步改进，R9、R10、R11、R12、R13和R14各自独立地为氘或氢。
作为本发明的进一步改进，R15和R16各自独立地为氘或氢。
作为本发明的进一步改进，R17、R18和R19各自独立地为氘或氢。
作为本发明的进一步改进，R20、R21、R22和R23各自独立地为氘或氢。
作为本发明的进一步改进，R24和R25各自独立地为氘或氢。
作为本发明的进一步改进，所述咪唑并喹唑啉化合物可选自如下任一结构，或其药学上可接受的盐：
Figure PCTCN2017087140-appb-000002
Figure PCTCN2017087140-appb-000003
Figure PCTCN2017087140-appb-000004
在另一优选例中，所述的化合物不包括非氘代的化合物。
本发明还公开了一种药物组合物，其含有药学上可接受的载体和如上所述的咪唑并喹唑啉化合物，或其晶型、药学上可接受的盐、水合物或溶剂合物。
本发明也涉及包含一种或多种本发明化合物的药物组合物。通过将其给药于需要的患者，这些药物组合物可以用于实现所需药学效果。
本发明中的“患者”是指需要治疗特定病况或病症的哺乳动物，包括人类。
本发明包括由药学可接受的载体和药学有效量的本发明化合物或其盐组成的药物组合物。药学可接受的载体优选相对地无毒性载体，并且在其浓度与有效成分的有效活性一致时对患者无害，这样可归因于所述载体的任何副作用不削弱有效成分的效用。化合物的药学有效量优选对治疗的特定病况产生效果或发挥影响的用量。
本发明的化合物可与熟知的药学可接受的载体一起给药，并采用任何有效的传统单元剂型，包括立即、缓慢和定时释放制剂，其给药方法包括口服、肠胃外给药、局部用药、鼻内投药、眼部给药、舌下给药、直肠给药、阴道给药等。
对于口服给药，可以将所述化合物配制成固体或液体制剂，如胶囊剂、丸剂、片剂、含片、锭剂、熔化物、散剂、溶液剂、混悬剂或乳剂，并且可以按照已知的生产药物组合物的方法配制。所述的固体单元剂型可以是普通的硬或软壳明胶胶囊型，含有例如表面活性剂、润滑剂和惰性填充剂如乳糖、蔗糖、磷酸钙和玉米淀粉。
在另一实施方式中，可以将本发明化合物和传统片剂基质如乳糖、蔗糖和玉米淀粉进行压片，组合以下成分：粘合剂，如阿拉伯树胶、玉米淀粉或明胶；崩解剂(用以在给药后帮助分解和溶解片剂)，如马铃薯淀粉、褐藻酸、玉米淀粉和瓜尔胶、西黄蓍胶和阿拉伯树胶；润滑剂(用以改善片剂成粒的流动性并且防止片剂物质粘附在片剂模具和模孔的表面)，如滑石、硬脂酸、或硬脂酸镁、硬脂酸钙或硬脂酸锌；染料；着色剂；以及调味剂(用以提高药片的感官质量并使得它们更易为患者接受)，如薄荷、冬青油或樱桃调味剂。用于口服液体剂型的适当赋形剂包括：磷酸二钙和稀释剂 如水和醇，例如，乙醇、苄醇和聚乙二醇，添加或不添加药学可接受的表面活性剂、助悬剂或乳化剂。各种其它材料可以用作包衣或者用以改变制剂单元的物理形态。例如，片剂、丸剂或胶囊可以覆有虫胶、糖或二者。
可分散的粉末和颗粒适合于配制成水混悬液。它们包含有效成分、分散剂或湿润剂、助悬剂和一种或多种防腐剂。适当的分散剂或湿润剂和助悬剂在上文中已举例列出。其它的赋形剂，例如上述的甜味剂、调味剂和着色剂也可以包含在其中。
本发明的药物组合物也可以采用水包油型乳剂。所述油相可以是一种植物油如液体石蜡，或者植物油的混合物。适当的乳化剂可以是：自然界存在的树胶如阿拉伯树胶和西黄蓍胶；自然界存在的磷脂如黄豆和卵磷脂；源于脂肪酸和己糖醇酐的酯或偏酯，如山梨糖醇酐单油酸酯；上述偏酯与氧化乙烯的缩合产物，例如，聚氧乙烯山梨糖醇酐单油酸酯。所述乳剂还可以包含甜味剂和调味剂。
所述药物组合物也可以是无菌的可注射水混悬液形式。这样的混悬液可以按照已知的方法用适当的分散剂或湿润剂和助悬剂配制。所述助悬剂如羧甲基纤维素钠、甲基纤维素、羟丙基甲基-纤维素、海藻酸钠、聚乙烯吡咯烷酮、西黄蓍胶和阿拉伯树胶。分散剂或湿润剂可以是自然界存在的磷脂，如卵磷脂、氧化烯与脂肪酸的缩合产物(如聚氧乙烯硬脂酸酯)、氧化乙烯与长链脂肪醇的缩合产物(如十七乙氧基鲸蜡醇)、氧化乙烯与偏酯(衍生自脂肪酸和己糖醇)的缩合产物(如聚氧乙烯山梨糖醇单油酸酯)、或氧化乙烯与偏酯(衍生自脂肪酸和己糖醇酐)的缩合产物(如聚氧乙烯山梨糖醇酐单油酸酯)。
所述无菌的可注射制剂还可以是在无毒性肠胃外用可接受的稀释剂或溶剂中的无菌的可注射溶液剂或混悬液。可以使用的稀释剂和溶剂是：如，水、林格溶液、等渗氯化钠溶液和等渗葡萄糖溶液。另外，传统地用无菌的非挥发性油作为溶剂或悬浮介质。为此，可以使用任何无刺激性的非挥发性油，包括合成的甘油单酯或甘油二酯。此外，脂肪酸如油酸可以用于配制可注射剂。
本发明的组合物还能以适用于直肠投药的栓剂型给药。通过将药物与适当的非刺激性赋形剂混合来配制这些组合物，所述赋形剂在常温下是固体而在直肠的温度下是液体，并且因此在直肠中融化释放出药物。这样的物质如可可油和聚乙二醇。
用于本发明方法中的另一种剂型是利用经皮递送装置。这种经皮贴片可以用于以受控量连续或间断地输注本发明的化合物。用于递送药剂的经皮贴片的结构和用法是本领域公知的(美国专利5,023,252号)。可以将所述贴片构建成用于连续性地、脉冲性地或按照需要递送药剂。
用于肠胃外给药的控释剂型包括已知的脂质体剂、聚合物微球体剂和聚合物凝胶剂。
可能需要或必要通过机械递送装置将药物组合物施药于患者。用于递送药剂的机械递送装置的 结构和用法是本领域公知的。直接技术，如直接施药于大脑，通常需要将药物递送导管安插入患者的脑室系统以避开血脑屏障。(美国专利5,011,472号中描述一种这样的可植入递送系统，用于将药剂传送至特定的身体解剖区域)。
本发明还包括同位素标记的化合物，等同于原始化合物在此公开。可以列为本发明的化合物同位素的例子包括氢，碳，氮，氧，磷，硫，氟和氯同位素，分别如2H，3H，13C，14C，15N，17O，18O，31P，32P，35S，18F以及36Cl。本发明中的化合物，或对映体，非对映体，异构体，或药学上可接受的盐或溶剂化物，其中含有上述化合物的同位素或其他其他同位素原子都在本发明的范围之内。本发明中某些同位素标记化合物，例如3H和14C的放射性同位素也在其中，在药物和底物的组织分布实验中是有用的。氚，即3H和碳-14，即14C，它们的制备和检测比较容易，是同位素中的首选。此外，较重同位素取代如氘，即2H，由于其很好的代谢稳定性在某些疗法中有优势，例如在体内增加半衰期或减少用量，因此，在某些情况下可以优先考虑。同位素标记的化合物可以用一般的方法，通过用易得的同位素标记试剂替换为非同位素的试剂，用示例中的方案可以制备。
本发明还公开了一种如上所述的咪唑并喹唑啉化合物的用途，其用于制备与磷脂酰肌醇3-激酶(PI3K)相关疾病的药物组合物。优选的，其用于制备抑制磷脂酰肌醇3-激酶(PI3K)介导的疾病的药物，例如癌症、细胞增殖性疾病、血管发生疾病、炎性疾病、自身免疫疾病、心血管疾病、神经变性疾病、代谢失调、伤害感受疾病、眼病、肺病或肾病。
本发明所述的细胞增殖性疾病包括，但不局限于，牛皮癣、瘢痕疙瘩及其它影响皮肤的增生、良性前列腺增生(BPH)、实体瘤(如乳腺癌、呼吸道癌、脑癌、生殖器官癌、消化道癌、尿道癌、眼癌、肝癌、皮肤癌、头和颈癌、甲状腺癌、副甲状腺癌以及它们的远端转移)，以及括淋巴瘤、肉瘤和白血病。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
与现有技术相比，本发明的有益效果为：
第一，采用本发明技术方案的咪唑并喹唑啉化合物，对磷脂酰肌醇3-激酶(PI3K)具有优异的抑制性。第二，通过氘代这一技术改变化合物在生物体中的代谢，使化合物具有更好的药代动力学参数特性。在这种情况下，可以改变剂量并形成长效制剂，改善适用性。第三，用氘取代化合物中的氢原子，由于其氘同位素效应，能够提高化合物在动物体内的药物浓度，以提高药物疗效。第四，用氘取代化合物中的氢原子，可以抑制某些代谢产物，提高化合物的安全性。
具体实施方式
下面对本发明的较优的实施例作进一步的详细说明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则份数和百分比为重量份和重量百分比。
实施例1制备2-氨基-N-[7-d3-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基] 嘧啶-5-甲酰胺(化合物14)
Figure PCTCN2017087140-appb-000005
具体合成步骤如下：
Figure PCTCN2017087140-appb-000006
步骤一：化合物2的合成。
依次将化合物1(10.0g,72.4mmo)、二氯甲烷(200mL)和N,N-二异丙基乙胺(DIPEA，12mL，79.6mmol)加入至一个250mL的圆底烧瓶中，待该反应液冷却至0℃后，加入2-(三甲基硅烷基)乙氧甲基氯(SEM-Cl，12.0g，72.4mmol)的二氯甲烷(100mL)溶液，室温下搅拌2小时后，减压移除溶剂，残留物通过柱色谱分离纯化得到化合物2为无色油状物9.37g，收率为48％。LC-MS:m/z＝269.1(M+1)+；1HNMR(300MHz,CDCl3)(δ/ppm)9.82(s,1H),7.43(s,1H),7.37(dd,J＝10.2Hz,1H),7.21(d,J＝8.4Hz 1H),6.78(s,1H),5.33(s,2H),3.75(t,2H),0.93(t,2H),0.00(s,9H)。
步骤二：化合物3的合成。
氮气保护下，依次将化合物2(9.37g,34.92mmol)、丙酮(200mL)、碳酸钾(12.23g,62.86mmol)和氘代碘甲烷(CD3I，3.9mL,45.41mmol)加入至圆底烧瓶中，在60℃下搅拌2小时，待原料反应完全后，冷却至室温，移除丙酮，加入二氯甲烷萃取，收集有机相后得到化合物3为无色油状物，共6.4g，收率为84％。LC-MS:m/z＝286.2(M+1)+。
步骤三：化合物4的合成。
将化合物3(8.4g,29.42mmol)和150mL二氯甲烷加入至圆底烧瓶中，冷却至0℃后，加入三氟乙酸(TFA,40mL)，室温下搅拌1小时，待原料反应完后冷却至0℃，逐滴加入饱和碳酸氢钠溶液淬灭反应，用二氯甲烷萃取干燥后得到化合物4为浅色固体，共4.38g，收率为96％。LC-MS:m/z＝156.2(M+1)+。
步骤四：化合物5的合成。
依次将三乙胺(Et3N,8mL)和乙酸酐(Ac2O,4mL,42.34mmol)逐滴加入至连续搅拌的化合物4(4.38g,28.23mmol)的二氯甲烷(100mL)溶液中，室温下搅拌1小时。待反应底物反应完全后，加水30mL后用二氯甲烷萃取，收集有机相过柱纯化得化合物5为白色固体，共3.5g，收率为63％。LC-MS:m/z＝198.1(M+1)+；1HNMR(300MHz,CDCl3)(δ/ppm)9.97(s,1H),7.52-7.49(m,2H),7.28-7.23(m,1H),2.36(s,3H)。
步骤五：化合物6的合成。
在0℃下将15mL发烟硝酸加入圆底烧瓶中，缓慢加入化合物5(3.4g,17.24mmol)，继续在0℃下搅拌2小时。待反应完全后，加入30mL冰水，用二氯甲烷萃取，收集有机相干燥后得到化合物6为黄色油状物，共1.62g，收率为39％。LC-MS:m/z＝243.1(M+1)+；1HNMR(300MHz,CDCl3)(δ/ppm)9.92(s,1H),7.72(d,J＝8.7Hz,1H),7.46(dd,J＝8.4Hz,1H),2.425(s,3H)。
步骤六：化合物7的合成。
将碳酸钾加入至化合物6(1.62g,6.68mmol)的20mL甲醇溶液中，室温下搅拌过夜，移除甲醇，加入10mL水后，滴加0.5mol/L盐酸溶液调节pH至中性后，用二氯甲烷萃取，收集有机相过柱纯化得到化合物7为黄色固体，共733mg，收率为94％。
LC-MS:m/z＝201.1(M+1)+；1HNMR(300MHz,CDCl3)(δ/ppm)11.96(br s,1H),7.69(d,J＝8.7Hz,1H),7.22(J＝8.7Hz,1H),3.90(s,3H)。
步骤七：化合物9的合成。
依次将碳酸铯(Cs2CO3，20g,61.38mmol)和化合物8(4g,24.44mmol)加入至化合物7(4g, 20.29mmol)的150mL乙腈溶液中，加热至85℃后反应4小时，冷却至室温后过滤得到化合物9为棕色固体，共3.9g，收率为59％。LC-MS:m/z＝325.2(M+1)+；1HNMR(300MHz,CDCl3)(δ/ppm)7.45(d,J＝9.0Hz,1H),7.12(d,J＝9.0Hz,1H),4.21(t,J＝6.0Hz,2H),3.70(t,J＝4.5Hz,4H),2.53(t,J＝6.0Hz,2H),2.47-2.44(m,4H),2.09-2.03(m,2H)。
步骤八：化合物10的合成。
将化合物9(3.9g,11.72mmol)加入至85mL醋酸(CH3COOH)中，冷却至0℃后，依次加入0.2mL水和铁粉(3.4g,60mmol)，室温下搅拌4小时，过滤并用醋酸洗涤滤饼，收集滤液用二氯甲烷萃取后得到化合物10为棕色固体，共3g，收率为85％。LC-MS:m/z＝295.2(M+1)+。
步骤九：化合物11的合成。
氮气保护下，将硫磺(815mg,25.48mmol)加入至化合物10(3g,10.19mmol)和乙二胺(20mL)中，加热至100℃并反应3小时，加入水后出现沉淀，过滤得到化合物11为白色固体，共2g，收率为58％。LC-MS:m/z＝338.2(M+1)+。
步骤十：化合物12的合成。
将化合物11(2g,5.93mmol)和三乙胺(Et3N,2.5mL)的二氯甲烷溶液(40mL)冷却至0℃，加入溴化腈(1.26g,11.90mmol)，室温下搅拌1小时，移除溶剂加入22mL乙酸乙酯过滤收集滤液，加入石油醚搅拌，过滤，收集滤液得到化合物12为黄色固体，共1.7g，收率为79％。直接用于下一步。
步骤十一：化合物14的合成。
依次将化合物13(207mg,1.49mmol)、六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷(PyBop,863mg,1.66mmol)和DIPEA(0.7mL,4.15mmol)加入至化合物12(600mg,1.66mmol)的二氯甲烷溶液(20mL)中，室温下搅拌过夜，加入20mL乙酸乙酯，过滤纯化干燥后得到化合物14为白色固体，共137mg，收率为17％。LC-MS:m/z＝484.2(M+1)+；1HNMR(300MHz,CDCl3+MeOH-d4)(δ/ppm)9.02(s,2H),7.56(d,J＝9.0Hz,1H),6.94(d,J＝9.0Hz,1H),4.22-4.17(m,6H),3.75(t,J＝4.5Hz,2H),2.63(t,J＝4.5Hz,4H),2.55(t,J＝4.5Hz,4H),2.12-2.09(m,2H),1.27-1.25(m,2H)。
生物活性测试
(1)激酶抑制活性测试。
根据文献J.Med.Chem.2013,56,1922-1939中讲述述的方法，对本发明化合物的激酶活性进行检测。实验结果表明，本发明实施例化合物对磷脂酰肌醇3-激酶(PI3K)显示出有意的抑制活性，IC50<20nM。
(2)代谢稳定性评价
微粒体实验：人肝微粒体：0.5mg/mL，Xenotech；大鼠肝微粒体：0.5mg/mL，Xenotech；辅酶(NADPH/NADH)：1mM，Sigma Life Science；氯化镁：5mM，100mM磷酸盐缓冲剂(pH为7.4)。
储备液的配制：精密称取一定量的化合物粉末，并用DMSO分别溶解至5mM。
磷酸盐缓冲液(100mM，pH7.4)的配制：取预先配好的0.5M磷酸二氢钾150mL和700mL的0.5M磷酸氢二钾溶液混合，再用0.5M磷酸氢二钾溶液调节混合液pH值至7.4，使用前用超纯水稀释5倍，加入氯化镁，得到磷酸盐缓冲液(100mM)，其中含100mM磷酸钾，3.3mM氯化镁，pH为7.4。
配制NADPH再生系统溶液(含有6.5mM NADP，16.5mM G-6-P，3U/mL G-6-P D，3.3mM氯化镁)，使用前置于湿冰上。
配制终止液：含有50ng/mL盐酸普萘洛尔和200ng/mL甲苯磺丁脲(内标)的乙腈溶液。取25057.5μL磷酸盐缓冲液(pH7.4)至50mL离心管中，分别加入812.5μL人肝微粒体，混匀，得到蛋白浓度为0.625mg/mL的肝微粒体稀释液。取25057.5μL磷酸盐缓冲液(pH7.4)至50mL离心管中，分别加入812.5μL SD大鼠肝微粒体，混匀，得到蛋白浓度为0.625mg/mL的肝微粒体稀释液。
样品的孵育：用含70％乙腈的水溶液将相应化合物的储备液分别稀释至0.25mM，作为工作液，备用。分别取398μL的人肝微粒体或者大鼠肝微粒体稀释液加入96孔孵育板中(N＝2)，分别加入2μL 0.25mM的的工作液中，混匀。
代谢稳定性的测定：在96孔深孔板的每孔中加入300μL预冷的终止液，并置于冰上，作为终止板。将96孔孵育板和NADPH再生系统置于37℃水浴箱中，100转/分钟震荡，预孵5min。从孵育板每孔取出80μL孵育液加入终止板，混匀，补充20μL NADPH再生系统溶液，作为0min样品。再向孵育板每孔加入80μL的NADPH再生系统溶液，启动反应，开始计时。相应化合物的反应浓度为1μM，蛋白浓度为0.5mg/mL。分别于反应10、30、90min时，各取100μL反应液，加入终止板中，涡旋3min终止反应。将终止板于5000×g，4℃条件下离心10min。取100μL上清液至预先加入100μL蒸馏水的96孔板中，混匀，采用LC-MS/MS进行样品分析。
数据分析：通过LC-MS/MS系统检测相应化合物及内标的峰面积，计算化合物与内标峰面积比值。通过化合物剩余量的百分率的自然对数与时间作图测得斜率，并根据以下公式计算t1/2和CLint，其中V/M即等于1/蛋白浓度。
Figure PCTCN2017087140-appb-000007
对本发明化合物及其没有氘代的化合物同时测验比较，评价其在人和大鼠肝微粒体的代谢稳定性。作为代谢稳定性的指标的半衰期及肝固有清除率如表1所示。表1中采用未经氘代的化合物Copanlisib(2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-5-甲酰胺)作为对照样品。如表1所示，通过与未经氘代的化合物Copanlisib对照，本发明化合物可以显著改善代谢稳定性。
表1
Figure PCTCN2017087140-appb-000008
(3)大鼠药代动力学实验
实验目的：研究大鼠给予2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-5-甲酰胺、实施例化合物后，考察本发明化合物的药代动力学行为。
实验动物：
种类及品系：SD大鼠等级：SPF级
性别及数量：雄性，6只
体重范围：180～220g(实际体重范围为187～197g)
来源：上海西普尔必凯实验动物有限公司
实验及动物合格证号：SCXK(沪)2013-0016。
实验过程：
在血样采集之前，预先在EDTA-K2抗凝管中加入20L的2M氟化钠溶液(酯酶抑制剂)，于80度烘箱内烘干后，置于4度冰箱存放。
大鼠，雄性，体重187～197g，随机分为2组，于实验前一天下午开始禁食过夜但可自由饮水，给药后4h给食物。A组给予RVT-101 3mg/kg，B组给予实施例化合物3mg/kg，分别于给药后15min、30min、1、2、3、5、8、10h从大鼠眼眶静脉取血100-200L左右，置于经EDTA-K2抗凝的0.5mL的Eppendorf管中，立即混匀，抗凝后，尽快将试管轻轻颠倒混匀5-6次后,血取好后放置在冰盒中，30min内把血样本在4000rpm，10min，4℃条件下离心分离血浆，收集全部血浆后立即于-20℃保存。所有时间点样品采集后测定每个时间点的血浆中的血药浓度。
根据上述所得的给药后平均血药浓度-时间数据，采用Winnonin软件，按非房室统计矩理论求算雄性SD大鼠分别i.g给予RVT-101(3mg/kg)、实施例化合物(3mg/kg)后的药代动力学相关参数。
实验表明，与2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-5-甲酰胺相比，本发明化合物具有更优的活性，并且具有优异的药代动力学性质，因此更适合作为抑制磷脂酰肌醇3-激酶的化合物。
以上内容是结合具体的优选实施方式对本发明所作的进一步详细说明，不能认定本发明的具体实施只局限于这些说明。对于本发明所属技术领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干简单推演或替换，都应当视为属于本发明的保护范围。

Claims (10)

  1. 一种取代的咪唑并喹唑啉化合物，其特征在于：如式(I)所示的咪唑并喹唑啉化合物，或其晶型、药学上可接受的盐、水合物或溶剂化合物，
    Figure PCTCN2017087140-appb-100001
    其中，R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23、R24和R25各自独立地为氢、氘或卤素；
    附加条件是，所述咪唑并喹唑啉化合物至少含有一个氘原子。
  2. 根据权利要求1所述的咪唑并喹唑啉化合物，其特征在于：R1、R2、R3、R4、R5、R6、R7和R8各自独立地为氘或氢。
  3. 根据权利要求1所述的咪唑并喹唑啉化合物，其特征在于：R9、R10、R11、R12、R13和R14各自独立地为氘或氢。
  4. 根据权利要求1所述的咪唑并喹唑啉化合物，其特征在于：R15和R16各自独立地为氘或氢。
  5. 根据权利要求1所述的咪唑并喹唑啉化合物，其特征在于：R17、R18和R19各自独立地为氘或氢。
  6. 根据权利要求1所述的咪唑并喹唑啉化合物，其特征在于：R20、R21、R22和R23各自独立地为氘或氢。
  7. 根据权利要求1所述的咪唑并喹唑啉化合物，其特征在于：R24和R25各自独立地为氘或氢。
  8. 根据权利要求1～7任意一项所述的咪唑并喹唑啉化合物，其特征在于：所述咪唑并喹唑啉化合物可选自如下任一结构，或其药学上可接受的盐：
    Figure PCTCN2017087140-appb-100002
    Figure PCTCN2017087140-appb-100003
    Figure PCTCN2017087140-appb-100004
  9. 一种药物组合物，其特征在于：其含有药学上可接受的载体和如权利要求1～8任意一项所述的咪唑并喹唑啉化合物，或其晶型、药学上可接受的盐、前药、立体异构体、同位素变体、水合物或溶剂合物。
  10. 一种如权利要求1～8任意一项所述的咪唑并喹唑啉化合物的用途，其特征在于：用于制备由磷脂酰肌醇3-激酶(PI3K)介导的疾病的药物，所述疾病包括：癌症、细胞增殖性疾病、血管发生疾 病、炎性疾病、自身免疫疾病、心血管疾病、神经变性疾病、代谢失调、伤害感受疾病、眼病、肺病或肾病。
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