WO2017202206A1 - Composé quinoléine substitué et composition pharmaceutique correspondante - Google Patents

Composé quinoléine substitué et composition pharmaceutique correspondante Download PDF

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Publication number
WO2017202206A1
WO2017202206A1 PCT/CN2017/083878 CN2017083878W WO2017202206A1 WO 2017202206 A1 WO2017202206 A1 WO 2017202206A1 CN 2017083878 W CN2017083878 W CN 2017083878W WO 2017202206 A1 WO2017202206 A1 WO 2017202206A1
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WO
WIPO (PCT)
Prior art keywords
compound
quinoline compound
acid
hydrogen
compound according
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PCT/CN2017/083878
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English (en)
Chinese (zh)
Inventor
王义汉
李焕银
Original Assignee
深圳市塔吉瑞生物医药有限公司
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Application filed by 深圳市塔吉瑞生物医药有限公司 filed Critical 深圳市塔吉瑞生物医药有限公司
Priority to CN201780004355.XA priority Critical patent/CN108290842B/zh
Publication of WO2017202206A1 publication Critical patent/WO2017202206A1/fr

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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
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/40—Nitrogen atoms attached in position 8

Definitions

  • the invention belongs to the technical field of medicine, and in particular relates to a quinoline compound and a composition comprising the same and use thereof.
  • Serotonin is a class of vasoactive amines that are widely present in the body and act on 5-HT receptors. According to the structure and function, 5-HT receptors can be divided into 7 families and 14 subtypes. The receptor subtypes involved in the learning and memory process are mainly 5-HT 1A , 5-HT 1B , 5-HT 2 , 5-HT 3 , 5-HT 5 , 5-HT 6 , 5-HT 7 subtypes. 5-HT is a relatively important monoamine neurotransmitter in the central nervous system. It participates in many physiological processes such as sensory sacral movement and behavior.
  • the 5-HT 6 receptor As a member of the 5-HT receptor family, the 5-HT 6 receptor is located almost entirely in the central nervous system, especially in the cerebral cortex, striatum, hippocampus, nucleus accumbens, and olfactory nodules. region.
  • the 5-HT 6 receptor is closely related to the CNS transmitter of the central nervous system, and can regulate Ach, Glu, DA, GABA, and the like.
  • AD Alzheimer disease
  • senile dementia an age-related neurodegenerative disease, also known as senile dementia. Its etiology and pathogenesis are unclear, the treatment effect is not good, and the quality of life of patients is seriously affected after the onset. . Therefore, more and more attention has been paid. It is estimated that there are about 35.6 million AD patients in the world in 2010. It is estimated that in another 40 years, one in every 85 people will be an AD patient.
  • the present invention discloses a quinoline compound, a composition comprising the same, and a use thereof, which have 5-HT 6 receptor inhibitory activity and have better pharmacodynamic/pharmacokinetic properties. .
  • a 5-HT 6 receptor antagonist such as a quinoline compound of formula (I), or a polymorph, pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic variation, hydrate thereof 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 and R 18 are each independently hydrogen, deuterium, halogen or trifluoromethyl;
  • the quinoline compound contains at least one deuterium 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 strontium isotope content of each of the R 9 , R 16 , R 17 and R 18 deuterated sites is at least 5%, preferably greater than 10%, more preferably greater than 15%, more preferably greater than 20%, and even more preferably greater than 25.
  • the five Rs contain hydrazine, more preferably sixteen R ⁇ , more preferably seventeen R ⁇ , more preferably eighteen R ⁇ .
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently hydrazine or hydrogen.
  • R 6 , R 7 and R 8 are each independently hydrazine or hydrogen.
  • R 9 and R 10 are each independently hydrazine or hydrogen.
  • R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 are each independently hydrazine or hydrogen.
  • the quinoline compound may be selected from any of the following structures, or a pharmaceutically acceptable salt thereof:
  • the invention also discloses a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a quinoline compound as described above, or a polymorph thereof, a pharmaceutically acceptable salt, a prodrug, a stereoisomer, an isotope A variant, hydrate or solvate.
  • the pharmaceutical composition is a tablet, a capsule, an oral liquid preparation, a powder, a granule, a lozenge, a reconstitutable powder, an injectable or infusible solution or suspension or a suppository.
  • Oral administration compositions are generally preferred.
  • compositions of the invention suitably prepared at ambient temperature and pressure are generally suitable for oral, parenteral or rectal administration.
  • the tablets and capsules for oral administration may be in unit dosage form and may contain conventional excipients such as binders, fillers, tableting lubricants, disintegrating agents, and pharmaceutically acceptable wetting agents.
  • the tablets may be coated according to methods known in the art of pharmaceutical technology.
  • the oral liquid preparation may be, for example, an aqueous or oily suspension, solution, emulsion, syrup or elixir, or may be a dry product which is reconstituted with water or other suitable excipients before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous excipients (which may include edible oils), preservatives, and, if desired, conventional flavoring or coloring agents.
  • liquid unit dosage forms are prepared using a compound of the invention, or a pharmaceutically acceptable salt thereof, and a sterile excipient.
  • the compound can be suspended or dissolved in the excipient depending on the excipient and concentration used.
  • the compound can be dissolved and filter sterilized, then infused into a suitable vial or ampoule and sealed. It is advantageous to dissolve adjuvants such as local anesthetics, preservatives and buffers in the excipient.
  • the composition can be frozen after injection into a vial and the water removed in vacuo.
  • the parenteral suspension is prepared in substantially the same manner, but instead of dissolving the compound in the excipient, the compound is suspended in the excipient and replaced by filtration. Sterilization can be achieved by exposing the compound to ethylene oxide prior to suspending the compound in a sterile excipient. It is advantageous to include in the composition a surfactant or wetting agent which promotes a homogeneous distribution of the compound.
  • the composition may contain from 0.1% to 99% by weight of active substance, preferably from 10% to 60% of active substance.
  • a suitable dose may be 0.05-1000 mg, more preferably 0.05-200 mg, for example, 20-40 mg; and, preferably, the above unit dose is administered once a day, although it may be required to be administered more than once a day; and Treatment can last for weeks or months.
  • the present invention also discloses the use of quinoline compounds as described above for the preparation of diseases associated with 5-HT 6 receptor, pharmaceutical compositions thereof.
  • it is used for the preparation of a medicament for inhibiting 5-HT 6 receptor mediated diseases such as depression, anxiety, Alzheimer's disease, age-related cognitive decline, ADHD, obesity, mildness Cognitive impairment, schizophrenia, cognitive impairment and stroke in schizophrenia.
  • halogen means F, Cl, Br, and I unless otherwise specified. More preferably, the halogen atom is selected from the group consisting of F, Cl and Br.
  • deuterated means that one or more hydrogens in the compound or group are replaced by deuterium; deuteration may be monosubstituted, disubstituted, polysubstituted or fully substituted.
  • deuteration may be monosubstituted, disubstituted, polysubstituted or fully substituted.
  • deuterated is used interchangeably with “one or more deuterated”.
  • non-deuterated compound means a compound containing a proportion of germanium atoms not higher than the natural helium isotope content (0.015%).
  • the invention also includes isotopically labeled compounds (also referred to as "isotopic variants"), 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.
  • 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.
  • Pharmaceutically acceptable salts include inorganic and organic salts.
  • a preferred class of salts are the salts of the compounds of the invention with acids.
  • Suitable acids for forming salts include, but are not limited to, mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid; formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, Organic acids such as fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid; Amino acids such as amino acid, phenylalanine, aspartic acid, and glutamic acid.
  • salts of the compounds of the invention with bases such as alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example magnesium or calcium salts), ammonium salts (for example lower alkanolammonium).
  • bases such as alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example magnesium or calcium salts), ammonium salts (for example lower alkanolammonium).
  • Salts and other pharmaceutically acceptable amine salts such as methylamine, ethylamine, propylamine, dimethylamine, trimethylamine, diethylamine, triethylamine, tert-butyl
  • a base amine salt an ethylenediamine salt, a hydroxyethylamine salt, a dihydroxyethylamine salt, a trihydroxyethylamine salt, and an amine salt formed of morpholine, piperazine, and lysine, respectively.
  • polymorph refers to a different arrangement of chemical drug molecules, generally expressed as the presence of a pharmaceutical material in a solid state.
  • a drug may exist in a plurality of crystalline forms, and different crystal forms of the same drug may have different dissolution and absorption in the body, thereby affecting the dissolution and release of the formulation.
  • solvate refers to a complex of a compound of the invention that is coordinated to a solvent molecule to form a specific ratio.
  • Hydrophilate means a complex formed by the coordination of a compound of the invention with water.
  • prodrug refers to a compound that is converted in vivo to an active form having its medical effect by, for example, hydrolysis in blood.
  • a prodrug is any covalently bonded carrier which, when administered to a patient, releases the compound of the invention in vivo.
  • Prodrugs are typically prepared by modifying functional groups that cleave the prodrug in vivo to yield the parent compound.
  • Prodrugs include, for example, hydroxyl, ammonia
  • the compound of the present invention having a thiol group or a thiol group bonded to any group, when administered to a patient, can be cleaved to form a hydroxy group, an amino group or a thiol group.
  • prodrugs include, but are not limited to, covalent derivatives of the compounds of the invention formed by the hydroxyl, amino or thiol functional groups thereof with acetic acid, formic acid or benzoic acid.
  • acetic acid formic acid or benzoic acid.
  • an ester such as a methyl ester, an ethyl ester or the like can be used.
  • the ester itself may be active and/or may hydrolyze under conditions in humans.
  • Suitable pharmaceutically acceptable in vivo hydrolysable esters include those which readily decompose in the human body to release the parent acid or its salt.
  • the compounds of the invention may include one or more asymmetric centers, and thus may exist in a variety of "stereoisomer" forms, for example, enantiomeric and/or diastereomeric forms.
  • the compounds of the invention may be in the form of individual enantiomers, diastereomers or geometric isomers (e.g., cis and trans isomers), or may be in the form of a mixture of stereoisomers, A racemic mixture and a mixture rich in one or more stereoisomers are included.
  • the isomers can be separated from the mixture by methods known to those skilled in the art, including: chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of a chiral salt; or preferred isomers can be passed Prepared by asymmetric synthesis.
  • HPLC high pressure liquid chromatography
  • the quinoline compound having the technical solution of the present invention has excellent inhibitory property to the 5-HT 6 receptor.
  • 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.
  • N-iodosuccinimide (NIS, 6.88 g, 30.58 mmol) was added to an acetic acid solution (20 mL) of 8-fluoroquinoline (Compound 1, 3.0 g, 20.39 mmol) under nitrogen, and heated. It was stirred to 80 ° C at this temperature overnight. After adding sodium sulfite (1.5 g) for 1 hour, the reaction was quenched by the addition of iodine, and after 1 hour, it was cooled to room temperature, filtered under low pressure, and the crystals were washed with acetic acid/water (1/2). g, yield was 69%.
  • LC-MS (APCI): m / z 293.9 (M + 1) +.
  • NIS (170 mg, 757 ⁇ mol) was added to a solution of the compound 7 (312 mg, 688 ⁇ mol) in acetic acid (2 mL), heated to 50 ° C and reacted at this temperature for 14 hours, then diluted with 30 mL of ethyl acetate, followed by water, hydrogen carbonate The sodium solution, the sulfurous acid solution, and the saturated aqueous sodium chloride solution were washed, and the organic phase was collected and purified by thin layer chromatography to obtain 8250 mg of a yellow solid, yield 63%.
  • Fetal bovine serum Fetal Bovine Serum (FBS) [Biowest #S1810-500]
  • Streptomycin Penicillin/Streptomycin (Pen/Strep) [Biowest#L0022-100]
  • Clozapine [Sigma #C6305-25MG]
  • Liquid Workstation Bravo liquid handling system (Agilent Technologies)
  • the medium is prepared as follows:
  • Resuscitation medium 500mL DMEM + 50mL FBS + 5mL Pen / Strep
  • test compound is incorporated into DMSO and configured to a solution of the specified concentration.
  • 10 nL of the indicated concentration of compound was transferred to a 384-well assay plate plus positive control (Clozapine, 30 mM) and negative control (DMSO); the foil was ready for use.
  • HEK293/5-HT 6 cells were cultured to approximately 90% confluence in a carbon dioxide incubator (37 degrees, 5% CO2), removed, the medium was aspirated, rinsed once with 5 mL of DPBS, and DPBS was discarded; Rinse once with 5 mL of 0.05% Trypsin-EDTA, aspirate; incubate for 2 minutes in a carbon dioxide incubator; after microscopic observation, gently slam the dish and confirm that the cells have dispersed.
  • Example number IC 50 (nM) Example number IC 50 (nM) Example 1 B Example 3 B Example 2 B Example 4 A
  • the compound of the present invention exhibited excellent inhibitory activity against 5-HT 6 (IC 50 of less than 10 nM, more preferably less than 1 nM). Therefore, the compounds of the present invention are effective drugs which are useful for diseases mediated by the 5-HT 6 receptor.
  • Microsomal experiments human liver microsomes: 0.5 mg/mL, Xenotech; rat liver microsomes: 0.5 mg/mL, Xenotech; mouse liver microsomes: 0.5 mg/mL, Xenotech; coenzyme (NADPH/NADH): 1 mM , Sigma Life Science; magnesium chloride: 5 mM, 100 mM phosphate buffer (pH 7.4).
  • 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.
  • 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 liver microsomes in human, rat and mouse was evaluated by comparing 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 2.
  • the undeuterated compound RVT-101 was used as a control sample in Table 2.
  • the compounds of the present invention can significantly improve metabolic stability by comparison with the undeuterated compound RVT-101.
  • EXPERIMENT OBJECTIVE To investigate the pharmacokinetic behavior of the compounds of the present invention after administration of RVT-101 and the compounds of the examples in rats.
  • 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 excellent pharmacokinetic properties as compared with RVT-101, and thus is more suitable as a compound for inhibiting anaplastic lymphoma kinase, and is therefore suitable for preparing a medicament for treating cancer.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé quinoléine substitué tel que présenté dans la formule (I), une composition pharmaceutique comportant ledit composé ou son polymorphe, son sel de qualité pharmaceutique, son promédicament, son stéréo-isomère, son variant isotopique, son hydrate ou son solvate, et son application. Le composé quinoléine substitué selon la présente invention et la composition pharmaceutique comportant ledit composé peuvent agir comme un antagoniste du récepteur 5-HT6, possèdent de bonnes caractéristiques de paramètres pharmacocinétiques et peuvent entrer dans la préparation d'un médicament destiné au traitement de la maladie d'Alzheimer.
PCT/CN2017/083878 2016-05-27 2017-05-11 Composé quinoléine substitué et composition pharmaceutique correspondante WO2017202206A1 (fr)

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CN201780004355.XA CN108290842B (zh) 2016-05-27 2017-05-11 一种取代的喹啉化合物及其药物组合物

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CN201610362199.1 2016-05-27
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1656075A (zh) * 2002-03-27 2005-08-17 葛兰素集团有限公司 喹啉衍生物和其作为5－ht6配体的用途

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* Cited by examiner, † Cited by third party
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GB0321473D0 (en) * 2003-09-12 2003-10-15 Glaxo Group Ltd Novel compounds
PT1667975E (pt) * 2003-09-26 2008-02-29 Glaxo Group Ltd Forma polimórfica de 3-fenilsulfonil-8-piperazin-1-il-quinolina

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1656075A (zh) * 2002-03-27 2005-08-17 葛兰素集团有限公司 喹啉衍生物和其作为5－ht6配体的用途

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CN108290842B (zh) 2021-04-06

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