CN109280056A - Chiral 3- quinuclidine ketone compounds, Preparation method and use - Google Patents

Chiral 3- quinuclidine ketone compounds, Preparation method and use Download PDF

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Publication number
CN109280056A
CN109280056A CN201710603967.2A CN201710603967A CN109280056A CN 109280056 A CN109280056 A CN 109280056A CN 201710603967 A CN201710603967 A CN 201710603967A CN 109280056 A CN109280056 A CN 109280056A
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inhibitor
general formula
pharmaceutically acceptable
isomers
prodrug
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张富尧
袁洪顺
神小明
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Shanghai Time Biotechnology Co Ltd
Selection Bioscience LLC
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Shanghai Time Biotechnology Co Ltd
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Priority to CN201710603967.2A priority Critical patent/CN109280056A/en
Priority to PCT/CN2018/096618 priority patent/WO2019015689A1/en
Publication of CN109280056A publication Critical patent/CN109280056A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • 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
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • 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
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Abstract

The present invention relates to or mixtures thereof such as general formula I-A, I-B compound represented, its pharmaceutically acceptable salt, isomers, solvate, polymorph, stable isotope derivatives or prodrug, preparation method and applications pharmaceutically, such as to the application in cancer, autoimmune disease treatment.

Description

Chiral 3- quinuclidine ketone compounds, Preparation method and use
Technical field
The present invention relates to a kind of chirality 3- quinuclidine ketone compounds and its isomers, prodrug or pharmaceutically acceptable salt, Stable isotope derivatives, pharmaceutical composition, preparation method and the purposes for treating related disease.
Background technique
The high mortality of cancer and to the drug resistance of the routine treatment of cancer be still human health cause face it is main Challenge.Therapeutic strategy new at present lays particular emphasis on discovery for the new non-chemical therapy of cancer specific targets.P53 gene is weight The tumor suppressor gene wanted, repair in cell cycle regulating, DNA, in terms of play key effect, and at least 50% Tumour in find that the p53 gene of mutation, most of chemotherapeutics by induced DNA damage need functional p53 to send out Its antitumor action is waved, and P53 mutation or indirect mechanism make p53 inactivation increase the drug resistance of conventional medicament, have to carry and dash forward Become p53 genetic tumour treatment be a major challenge faced at present, also therefore p53 become antineoplastic an important target spot Gene.
P53 gene has wild type and two kinds of saltant type, and wild type p53 is tumor suppressor gene important in human body, but is mutated Type p53 molecular conformation changes and loses cancer suppressing function, but also can inhibit the transcriptional activity of wild type p53, loses it To the inhibiting effect of cell growth, so as to cause cell distorted proliferation and it is converted into malignant cell, it is close with p53 gene mutation at present It cuts relevant malignant tumour and has liver cancer, gastric cancer, colon cancer, the cancer of the esophagus, lung cancer, breast cancer, lymph cancer, oophoroma, cervical carcinoma Deng.At present using p53 as the predominantly following several modes of action of the drug of target spot, first is that gene therapy, such as drug Gendicine and Advexin；Second is that p53-MDM2 mechanism of action, interferes the synthesis of p53-MDM2 compound to prevent p53 by small-molecule drug The degradation of proteins ubiquitin, such as drug Idasanutlin, HDM-201 and AMG-232；Third is that Mutant p 53 Protein conformation changes Become, small molecule compound is combined by way of covalent bond with amino acid, to change or modify the structure of p53, makes it Conformation changes, and is from compound to restore tumor suppressor gene active function, such as compound APR-246/PRIMA-1MET It is screened in library, is metabolized to methylene quinuclidone MQ in vivo, becomes Michael receptor, pass through cysteine protein Thiol group carry out addition and combine to form covalent bond modifying DNA, change p53 protein conformation, so that activated transcription is active, mesh The preceding compound enters clinical second phase research, for treat the cancer of the esophagus, prostate cancer, acute myelogenous leukemia, oophoroma and Myeloproliferative tumour etc..
APR-246 is the racemization type 3- quinine that Mutation p53 genetic tumour is carried for treatment in clinical investigation phase Ring ketone compounds, two enantiomters in raceme often have different bioactivity, pharmacokinetic properties, poison Side effect and metabolic stability, therefore 3- quinuclidine ketone compounds with optical activation are developed with importance and necessity Property.
Summary of the invention
The object of the present invention is to provide chiral 3- quinuclidine ketone compounds, preparation method and uses.
In a first aspect, the present invention relates to it is a kind of as general formula I-A, I-B compound represented, its pharmaceutically acceptable salt, Or mixtures thereof isomers, solvate, polymorph, stable isotope derivatives or prodrug；
In formula,
R is selected from substituted or unsubstituted, unbranched or has a branch, saturated or unsaturated C1-10Alkyl or C3-12Naphthenic base, Substituted or unsubstituted aryl；Substituted or unsubstituted saturated or unsaturated heterocycle；-L1-L2, L1Selected from substituted or unsubstituted C1-10Alkyl, L2Selected from aryl or heterocycle, hetero atom is selected from N, O, S or P in the heterocycle.
In a preference of the invention, R is selected from substituted or unsubstituted C1-10Alkyl, it is preferably substituted or unsubstituted C1-6Alkyl, such as methyl, trifluoromethyl, ethyl, propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl etc..
In a preference of the invention, R is selected from-L1-L2, L1Selected from C substituted or unsubstituted1-6Alkyl, more preferable C1-4 Alkyl, preferably L2Selected from aryl or heterocycle, such as benzyl, phenylethyl, phenyl propyl, phenyl butyl etc..
In a preference of the invention, R is selected from methyl.
In a preference of the invention, the compound is had the following structure:
Second aspect prepares that general formula I-A, I-B compound represented, its is pharmaceutically acceptable the present invention also provides a kind of The method of or mixtures thereof salt, isomers, solvate, polymorph, stable isotope derivatives or prodrug, this method packet It includes:
3- quinuclidone under alkaline condition, reacts to obtain racemization general formula I-C compound with first aldehyde and alcohol, general formula I-C can Chiral separation, which is carried out, by chiral column or chemical resolution method obtains the general formula compound I-A and I-B of two single configurations, wherein The definition of R group is as defined in claim 1.
The reagent of the alkaline condition of offer includes organic base and inorganic base, and the organic bases include but is not limited to six Two silicon substrate lithium amide of methyl, sodium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamine, normal-butyl Lithium, s-butyl lithium, triethylamine, pyridine, 2,6- lutidines, N, N- diisopropyl ethyl amine, potassium tert-butoxide, sodium tert-butoxide, Tert-butyl alcohol lithium, tetrabutyl ammonium fluoride or N- methylmorpholine etc..The inorganic base includes but is not limited to potassium carbonate, carbonic acid Sodium, sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium fluoride, cesium carbonate, lithium carbonate, potassium phosphate, sodium hydride or hydrogen Change potassium etc..
The third aspect, the present invention relates to a kind of pharmaceutical composition, the pharmaceutical composition includes a effective amount of according to power Benefit require 1 described in or mixtures thereof general formula I-A, I-B compound represented, its pharmaceutically acceptable salt, isomers, solvent Compound, polymorph, stable isotope derivatives or prodrug and pharmaceutically acceptable carrier, diluent or excipient；
Fourth aspect, the present invention relates to described in first aspect general formula I-A, I-B compound represented, it can pharmaceutically connect Or mixtures thereof the salt received, isomers, solvate, polymorph, stable isotope derivatives or prodrug or the third aspect The pharmaceutical composition can answer in the drug by P53 mutation-related diseases in preparation for preventing, alleviating and/or treat With.
The present invention is further, described to be selected from cancer, diseases associated with inflammation, autoimmune by P53 mutation-related diseases The drug of disease, cardiovascular disease, heart disease, virus infection etc..
The present invention is further, and the cancer is selected from oophoroma, prostate cancer, myeloma (such as: myeloproliferative disorder), food Pipe cancer, gastric cancer, acute myeloid leukemia, chronic myelomonocytic leukemia, acute or chronic leukaemia etc..
5th aspect, the present invention relates to general formula I-A, I-B compounds represented, its pharmaceutically acceptable salt, isomers Or mixtures thereof, solvate, polymorph, stable isotope derivatives or prodrug can be with another or a variety of anticancers Agent is used in combination.
The present invention is further, and the anticancer agent is selected from alkylating agent, platinum medicine, topoisomerase enzyme inhibitor, DNA methyl Transferase, liposome, alkaloid, antibody drug, hormone anticancer agent, proteasome inhibitor, hdac inhibitor, the suppression of CDK kinases Preparation, VEGFR or EGFR inhibitor, m-TOR inhibitor, PI3K kinase inhibitor, B-Raf inhibitor, PARP inhibitor, c- Met kinase inhibitor, ALK kinase inhibitor, AKT inhibitor, ABL inhibitor, FLT3 inhibitor, PD-1 monoclonal antibody, PD-L1 monoclonal antibody Deng.
6th aspect, the present invention relates to general formula I-A, I-B compounds represented, its pharmaceutically acceptable salt, isomers Or mixtures thereof, the drug of solvate, polymorph, stable isotope derivatives or prodrug in preparation treating cancer uses On the way, wherein the drug can be with another or the use of a variety of anti-cancer agent in conjunction.
The present invention is further, the anticancer agent be selected from alkylating agent (such as: cyclophosphamide, mustine hydrochlcride, dibromannitol, Carmustine, Dacarbazine, melphalan etc.), platinum medicine (such as: cis-platinum, carboplatin, epitrazide, Nedaplatin, oxaliplatin, lobaplatin Deng), (such as: topotecan, iritican, rubitecan, Yi Sha are replaced topoisomerase enzyme inhibitor for health, Lurtotecan, lucky horse Health, Diflomotecan), DNA/RNA synthetic inhibitor (such as: 5-Fluoracil, 5-FU etc.), dnmt rna (such as: Azacitidine, Decitabine etc.), liposome (such as: PLD), metabolic antagonist (such as: methotrexate (MTX), capecitabine, training U.S. bent plug etc.), alkaloid (such as: docetaxel, taxol, vincaleukoblastinum), antibody drug (such as: the bent appropriate list of trastuzumab, pa Anti-, bevacizumab etc.), hormone anticancer agent (such as: Leuprorelin, dutasteride, dexamethasone), proteasome inhibitor (such as: Borax helps rice, Ai Shazuo meter, lenalidomide etc.), CDK kinase inhibitor (such as: palbociclib, ribociclib), VEGFR or EGFR inhibitor (such as: Afatinib, Imatinib, Gefitinib, Tarceva), m-TOR inhibitor (such as: according to Wei Mosi, sirolimus etc.), PI3K kinase inhibitor (such as: Ai Lalisi), B-Raf inhibitor (such as: Sorafenib, dimension sieve Fei Ni, auspicious cut down luxuriant and rich with fragrance Buddhist nun etc.), other PARP inhibitor (such as: olaparib, niraparib), (such as: west is up to benzene for hdac inhibitor Amine, pabishta, Vorinostat etc.) c-Met kinase inhibitor (such as: gram azoles replace Buddhist nun), (such as: color is auspicious to be replaced ALK kinase inhibitor Buddhist nun, Ah coming replace Buddhist nun etc.), AKT inhibitor (such as: piperazine Li Fuxin), ABL inhibitor, FLT3 inhibitor, PD-1 monoclonal antibody (such as: Opdivo, Keytruda etc.), PD-L1 monoclonal antibody (such as: Atezolizumab).
Detailed description of the invention
Unless stated to the contrary, otherwise following to be had the meaning that with term in the specification and in the claims
Term " alkyl " refers to the aliphatic hydrocarbon groups of saturation, the linear chain or branched chain group including 1~20 carbon atom.It is excellent Select the alkyl of 1~10 carbon atom, more preferable 1~8 carbon atom, non-limiting embodiments include but is not limited to: methyl, ethyl, N-propyl, normal-butyl, isobutyl group, tert-butyl, sec-butyl, n-pentyl, 2- methyl butyl, 3- methyl butyl, 1,1- dimethyl propylene Base, 1,2- dimethyl propyl, 2,2- dimethyl propyl, 1- ethyl propyl, n-hexyl, 2- methyl amyl, 3- methyl amyl, 4- first Base amyl, 1,1- dimethylbutyl, 1,2- dimethylbutyl, 2,2- dimethylbutyl, 1,3- dimethylbutyl, 2,3- dimethyl Butyl, 3,3- dimethylbutyl, 1,1,2- thmethylpropyl, 1- Ethyl-2-Methyl propyl, n-heptyl, 2- methylhexyl, 3- first Base hexyl, 4- methylhexyl, 5- methylhexyl, 2,2- dimethyl amyl group, 2,3- dimethyl amyl group, 2,4- dimethyl amyl group, 3, 3- dimethyl amyl group, 3,4- dimethyl amyl group, 2- ethylpentyl, 3- ethylpentyl, good fortune base, nonyl, decyl, undecyl, ten Dialkyl group and their various isomers etc..Alkyl can be substituted or unsubstituted, when substituted can be any It is substituted on workable tie point, the substituent group is preferably one or more groups, independently selected from alkyl, halogen, hydroxyl Base, sulfydryl, cyano, alkenyl, alkynyl, alkoxy, alkane sulfydryl, alkyl amino, nitro, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl Base, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkanes sulfydryl, heterocycle alkane sulfydryl, oxo base, amino, halogenated alkyl, hydroxyalkyl, carboxyl or Carboxylate etc..When " alkyl " and its prefix use here, all comprising the saturated carbon key of straight chain and branch.
Term " naphthenic base " refers to the unsaturated monocycle of saturation or part or polycyclic cyclic substituents, including 3~20 carbon originals Son, preferably 3~12 carbon atoms, more preferable 3~10 carbon atoms most preferably include 3~6 carbon atoms, monocyclic cycloalkyl Non-limiting embodiments include but is not limited to: cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, hexamethylene two Alkenyl, suberyl, cyclooctyl etc..The non-limiting embodiments of polycyclic naphthene base include but is not limited to the ring of loop coil, condensed ring and bridged ring Alkyl.Naphthenic base can be substituted or unsubstituted, and when substituted, the substituent group is preferably one or more groups, Independently selected from alkyl, halogen, hydroxyl, sulfydryl, cyano, alkenyl, alkynyl, alkoxy, alkane sulfydryl, alkyl amino, nitro, cycloalkanes Base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkanes sulfydryl, heterocycle alkane sulfydryl, oxo base, amino, Halogenated alkyl, hydroxyalkyl, carboxyl or carboxylate etc..
Term " aryl " refers to the conjugated hydrocarbon ring system group of any 6~18 stable carbon atoms, preferably 6~10 carbon originals Son can be the aromatic group, such as phenyl, naphthalene and anthracene etc. of monocycle, bicyclic, tricyclic or more, the aryl rings Can condense with heteroaryl, Heterocyclylalkyl or cycloalkyl ring on.Aryl can be it is substituted or unsubstituted, when substituted, institute Stating substituent group is preferably one or more groups, independently selected from alkyl, halogen, hydroxyl, sulfydryl, cyano, alkenyl, alkynyl, alkane Oxygroup, alkane sulfydryl, alkyl amino, nitro, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, ring Alkane sulfydryl, heterocycle alkane sulfydryl, oxo base, amino, halogenated alkyl, hydroxyalkyl, carboxyl or carboxylate etc..
Term " heterocycle " refers to monocycle, bicyclic, tricyclic or tetracyclic ring system, including thick and ring system, bridged-ring system or loop coil body It is that for one or more atoms individually optionally replaced hetero atom, hetero atom is selected from nitrogen, oxygen, sulphur, phosphorus and boron in middle ring It can be fully saturated or comprising one or more degrees of unsaturation, but the non-aromatic same clan Deng, ring；Nitrogen, carbon in its heterocycle, Phosphorus or sulphur atom are optionally oxidized；Nitrogen-atoms is optionally quaternary ammoniated；Heterocyclic system can in any hetero atom or It is connected in main structure to form stable compound on carbon atom.Hydrogen atom individually optional ground quilt on one or more rings Replaced one or more substituent groups described in the invention.The example of heterocycle includes but is not limited to: pyrrolidinyl, pyrazolidine Base, morpholinyl, piperazinyl, piperidyl, thio-morpholinyl, pyranose, THP trtrahydropyranyl, imidazolidinyl, indolinyl, octahydro Indyl, octahydro isoindolyl, thiazolidinyl, isothiazole alkyl, isoxazolidinyl, azetidinyl etc..
Term " heteroaryl " refers to that the carbon atom at least one ring is formed by fragrance by the hetero atom displacement selected from N, O or S Ring system, preferably 5~7 unit monocycle structures or 7~12 membered bicyclic structures, more preferably 5~6 unit's heteroaryls, such as pyrrole radicals, Imidazole radicals, pyridyl group, pyrimidine radicals, thiazolyl, thienyl, pyrazinyl, triazolyl, tetrazole radical, oxazolyl, indazolyl etc., it is described Heteroaryl ring can condense with aryl, Heterocyclylalkyl or cycloalkyl ring on.Heteroaryl can be substituted or unsubstituted, work as quilt When substitution, the substituent group is preferably one or more groups, independently selected from alkyl, halogen, hydroxyl, sulfydryl, cyano, alkene Base, alkynyl, alkoxy, alkane sulfydryl, alkyl amino, nitro, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle Alkoxy, cycloalkanes sulfydryl, heterocycle alkane sulfydryl, oxo base, amino, halogenated alkyl, hydroxyalkyl, carboxyl or carboxylate etc..
" substituted " refers to that one or more hydrogen or D-atom in group, preferably 1~5 hydrogen or D-atom are only each other On the spot replaced the substituent group by respective number.
" pharmaceutically acceptable salt " be refer to retain the biological effectiveness of free alkali and without other toxic side effects, it Can be acidic-group, basic group or amphiprotic group, non-limiting embodiments include but is not limited to: ackd salt include hydrochloride, Hydrobromate, sulfate, pyrosulfate, disulfate, sulphite, bisulfites, phosphate, dibasic alkaliine, phosphoric acid Dihydric salt, metaphosphate, pyrophosphate, nitrate, acetate, propionate, caprate, caprylate, formates, acrylates, Isobutyrate, caproate, enanthate, oxalates, malonate, succinate, suberate, benzoate, methyl benzoic acid Salt, phthalate, maleate, mesylate, tosilate, benzene sulfonate, (D, L)-tartaric acid, citric acid Salt, Malaysia-hydrochlorate, (D, L-) malate, fumarate, stearate, oleate, cinnamate, laruate, glutamic acid Salt, aspartate, fluoroform sulphonate, tonsillotome hydrochlorate, anti-sepsis hydrochlorate, salicylate etc..When the compounds of this invention contains Acidic-group is that pharmaceutically acceptable salt can also include: alkali metal salt (such as sodium salt or sylvite), alkali salt (such as calcium salt or magnesium salts), organic alkali salt (such as alkylaryl Ammonia, amino acid etc.).
" solvate " refers to one or more solvent molecules and the compound of the present invention is formed by aggregation (or association Object).The solvent of the solvate of formation includes, but are not limited to: water, dimethyl sulfoxide, methanol, ethyl alcohol, isopropanol, acetic acid etc..
" polymorph " refers to the compound of the present invention under solid states since there are two or more differences point The different solid crystal phases of son arrangement and generation, it may exist single crystal form or polymorph mixture.
" stable isotope derivatives " refer to that the arbitrary hydrogen atom of the compound of the present invention replaces institute by 1~5 D-atom Obtained isotope substitutive derivative or arbitrary carbon atom is by 1~3 C14Atom replaces obtained isotope to replace derivative Object or arbitrary oxygen atom are by 1~3 O18Atom replaces obtained isotope derivatives.
" prodrug " indicates to be converted under physiological conditions (such as in vivo) or through solvolysis of the invention The compound of bioactive compound, it can be understood as pharmaceutically acceptable metabolic precursor thereof.Prodrug can be inert matter Or specific activity parent compound activity is small, but can convert rapidly in vivo and generate parent compound of the invention, it can be with Improve its solubility in animal body and certain metabolic characteristics, prodrug includes such as amino protecting group, carboxyl-protecting group, phosphorus Lipid etc..
" pharmaceutical composition " refer to containing one or more compounds described herein or its physiologically pharmaceutical salt or The mixture and the pharmaceutical carrier of other components such as physiology and excipient of pro-drug and other chemical constituents.Medicine The purpose of compositions is the administration promoted to organism, conducive to active constituent absorption and play bioactivity.
" isomers " refers to stereoisomer, comprising: enantiomter and diastereoisomer, cis-trans-isomer are non-right Reflect one kind of isomers.Isomers in this clearly demarcated compound can be its enantiomter, diastereoisomer and it Any mixture, exist including free or formation at salt.
The abbreviation of any blocking group, amino acid and other compounds used in the present invention, unless otherwise indicated, all with Subject to their usually used, generally acknowledged abbreviations, or refer to IUPAC-IUBC Commission on Biochemical Nomenclature (referring to Biochem.1972,11,942-944).
Specific embodiment
This explanation is further described below by embodiment, but these embodiments are not intended to limit the scope of the invention.
Test method without specific conditions in the embodiment of the present invention, usually according to conventional methods and conditions, or according to Condition proposed by raw material or commodity manufacturer.The reagent in specific source is not specified, for the conventional reagent of market purchase.
The structure of all compounds of the present invention can be determined by nuclear magnetic resonance (NMR) or mass spectrum (MS).NMR is displaced (δ) With 10-6(ppm) unit record.The determining instrument of NMR is that Bruker AVANCE-400 spectrometer carries out.That tests is deuterated molten Agent is deuterated chloroform (CDCl3), deuterated methanol (MeOD), deuterated dimethyl sulfoxide (DMSO-D6), inside it is designated as tetramethylsilane (TMS)。
Low resolution mass spectrometry (MS) is measured by Agilent 6120quadruple LCMS mass spectrograph.
The measurement of HPLC purity is by 1260/1220 chromatograph (Agilent of Agilent high performance liquid chromatograph Agilent 3.5 4.6mm × 150mm × 3 μm pHlex ODS μ m 4.6mm × 150mm or Boston Zorbax Bonus RP or Sepax BR-C18(4.6mm x 150mm x3μm)
The purifying of the compounds of this invention and its intermediate can be used conventional preparation scale HPLC, silica gel plate, column chromatography or It is isolated and purified using quick separating instrument.
Tlc silica gel plate is thin using the Yantai Huanghai Sea, the HSGF254 or Qingdao GF254 silica gel plate of the new promise chemical industry in Yantai The specification that the silica gel plate that layer chromatography (TLC) uses uses is 2.5x 5cm, 0.2mm~0.25mm, thin-layer chromatography partition method (pre-TLC) specification that purified product uses is 1mm or 0.4mm~0.5mm, 20x 20cm.
The specification that column chromatography (silica gel column chromatography) generally uses is 100~200 mesh or 200~300 mesh or 300~400 mesh.
The instrument model that quick separating instrument uses is Agela Technologies MP200, and chromatographic column specification is generally Flash column silica-CS。
The instrument that preparation scale HPLC (Pre-HPLC) is used is Gilson GX-281, column model: Welch ultimate XB-C18 21.2mm X 250mm X 10μm。
Model CHIRALCEL OD-H, OJ-H CHIRALPAK AD-H, the AS-H 4.6mm X of chiral test pole 5 μm of 250mm X, preparation column type number is CHIRALCEL OD-H, OJ-H or CHIRALPAKAD-H, AS-H 10mm X 5 μm of 250mm X,
Known starting material of the invention can be used or be synthesized according to methods known in the art, or from supplier Sigma-Aldrich, ACROS, Alaf, TCI, lark prestige, the resistance to Jilin Chemical of peace, splendid remote chemistry, Mai Kelin, think opinion on public affairs Xue Deng company Purchase gained.
Anhydrous solvent such as anhydrous tetrahydro furan, anhydrous methylene chloride, anhydrous n,N-dimethylacetamide etc. is all purchased from upper State chemical company.
Without specified otherwise in embodiment, reaction is usually to carry out in nitrogen or argon atmosphere, and nitrogen or argon atmosphere are Refer to that reaction flask connects the nitrogen of an about 1L volume size or the balloon of argon gas and carries out pumping displacement three times.
Without specified otherwise in embodiment, the temperature of reaction is room temperature, and temperature is 15~25 DEG C.
Reaction in embodiment generally uses LCMS or TLC to be monitored, and wherein LCMS instrument is shown in upper described, TLC institute The solvent system used is general are as follows: methylene chloride and methanol, petroleum ether and ethyl acetate, methylene chloride and ethyl acetate, stone The volume ratio of the systems such as oily ether and methylene chloride, ethyl acetate and methanol, solvent is different according to the polarity of compound and is adjusted The alkali (such as triethylamine or 37% ammonium hydroxide etc.) or sour (such as acetic acid etc.) of a small amount of (0.1%~10%) can also be added in section It is adjusted.
Prep-TLC, column chromatography or prep-HPLC system, the eluting solvent system that purifying compound uses are general are as follows: Methylene chloride and methanol, petroleum ether and ethyl acetate, methylene chloride and ethyl acetate, petroleum ether and methylene chloride, ethyl acetate It is adjusted with systems, the volume ratios of solvent such as methanol according to the polarity difference of compound, a small amount of (0.1% can also be added ~10%) alkali (such as triethylamine or 37% ammonium hydroxide etc.) or sour (such as acetic acid etc.) is adjusted.
Embodiment 1:
Racemization 2- (methylol) -2- (methoxy) quinuclidine -3- ketone
At 25 DEG C, 3- Quinuclidinone hydrochloride (50.0g), potassium carbonate (50.0g), 37% formaldehyde (105mL) are mixed in first In pure and mild aqueous systems, be heated to 70 DEG C of reaction 5h, reaction system be cooled to room temperature, with aq.NaOH adjust pH to 12~13, two Chloromethanes extraction, is concentrated to give crude product, and column chromatographic purifying obtains racemization 2- (methylol) -2- (methoxy) quinuclidine -3- ketone, 24.0g, yield 40%.
MS (ESI), m/z, 200.1 [M+H]+
1H NMR (400MHz, CDCl3) δ (ppm) 3.96 (d, J=11.8Hz, 1H), 3.88-3.73 (m, 3H), 3.39 (s, 3H), 3.37-3.25 (m, 2H), 3.06-2.88 (m, 3H), 2.39 (dd, J=6.0,3.0Hz, 1H), 2.10-1.94 (m, 4H)
Embodiment 2:2- (methylol) -2- (methoxy) quinuclidine -3- ketone (enantiomter 1)
By raceme 2- (methylol) -2- (methoxy) quinuclidine -3- ketone chiral column CHIRALPAK AS-H (10mm x 250mm, 5 μm) carries out separation preparation, obtains 2- (methylol) -2- (methoxy) quinuclidine -3- ketone (mapping Isomers 1) (ee > 98%).
1H-NMR (400MHz, CDCl3) δ (ppm) 3.98 (d, J=11.8Hz, 1H), 3.88-3.75 (m, 3H), 3.41 (s, 3H), 3.33 (ddd, J=16.6,7.8,4.0Hz, 2H), 3.06-2.84 (m, 3H), 2.42 (p, J=3.0Hz, 1H), 2.15- 1.91 (m, 4H)
Embodiment 3:2- (methylol) -2- (methoxy) quinuclidine -3- ketone (enantiomter 2)
By raceme 2- (methylol) -2- (methoxy) quinuclidine -3- ketone chiral column CHIRALPAK AS-H (10mm x 250mm, 5 μm) carries out separation preparation, obtains 2- (methylol) -2- (methoxy) quinuclidine -3- ketone (mapping Isomers 2) (ee > 95%).
1H-NMR (400MHz, CDCl3) δ (ppm) 3.97 (d, J=11.8Hz, 1H), 3.88-3.74 (m, 3H), 3.44- 3.36 (m, 3H), 3.38-3.27 (m, 2H), 3.05-2.82 (m, 3H), 2.40 (dd, J=6.0,3.0Hz, 1H), 2.14-1.93 (m, 4H)
Embodiment 4-19:
According to the synthetic method of Examples 1 to 3 and using corresponding starting material, the change of embodiment 4~19 is prepared Close the following table of object:
20 H1299 cell proliferation active testing of experimental example
Cell proliferation activity is tested by the following method:
Material and instrument used in this experiment:
RPMI1640 (CORNING-CELLGRO, #10-041-CVR)
Fetal Bovine Serum (BIOSERA, #FB-1280)
CellTiter-Glo Luminescent Cell Viability Assay (Promega, #G7572)
96-well plate (Corning, #3788)
96-well plate (Corning, #3797)
96-well plate, black (Corning, #3904)
Backing Tape, white (PE, #6005199)
DMSO (Sigma, #D2650)
Experimental method and step
1st day plating cells
1. trypsinized simultaneously determines cell density；
2. cell slurries are diluted to required volume with the density of optimization；
3. the cell slurries in 90 holes μ l/ are assigned in assay plate；
4. in 37 DEG C, 5%CO2With cell incubation 24 hours under wet condition.
2nd day addition compound
1. preparing reference compound, tested in 100%DMSO solution according to plate figure (final concentration 200x)；
2. shifting on the compound to the intermediate plate of 95 μ l of 5 μ l (concentration 10x)；
3. shifting on the compound to 9 test boards of 10 μ l (concentration 1x)；
4. in 37 DEG C, 5%CO2Be incubated under wet condition.
It is imaged within 5th day
1. using first room temperature equilibrium analysis reagent 30 minutes；
2. adding on 5 μ l cell titer-Glo reagents to each orifice plate and shaking 10 minutes promotion cell lysis；Compound arrive On the intermediate plate of 95 μ l (concentration 10x)；
3. hatching 2 minutes stabilized illumination signals；
4. reading light-emitting data on Envision, interval time 0.5s.
Data processing
Inhibiting rate=(Max signal-Compound signal)/(Max signal-Min signal) × 100
The cell proliferation activity of the compounds of this invention pass through more than experimental method be measured, measure Compound cellular suppression Make activity (IC50) see the table below :+indicate 100 μM of >, ++ indicate 50-100 μM, +++ indicate 10-50 μM, ++++indicate 1-10 μM ,+ ++++indicate 1 μM of <.
The experimental results showed that chipal compounds are substantially better than racemoid (implementation to the inhibitory activity of tumour cell Example 3 is relative to embodiment 1), there are apparent difference for inhibitory activity of the chiral isomer of different chiral configurations to tumour cell (embodiment 3 is relative to embodiment 2；Embodiment 7 is relative to embodiment 6；Embodiment 11 is relative to embodiment 10；13 phase of embodiment For embodiment 12；Embodiment 17 is relative to embodiment 16；Embodiment 19 is relative to embodiment 18)
The measurement of 21 pharmacokinetics in rats of experimental example
1. experiment abstract
Using SD rat as animal subject, after giving embodiment compound using LC/MS/MS method measurement rat intravenous and stomach-filling Drug concentration in different moments blood plasma evaluates it to study the compounds of this invention in the intracorporal pharmacokinetics behavior of rat Characteristics of pharmacokinetics.
2. experimental program
2.1 for reagent product:
1,2,3,10,11,14,15 compound of the embodiment of the present invention
2.2 for trying animal
Healthy adult male SD (Sprague-Dawley) rat, each 3 of each test compound, 6-9 week old, weight 250 ± 50g is purchased from Shanghai Slac Experimental Animal Co., Ltd..
2.3 prepare for reagent object
Appropriate amount of sample is weighed, 0.5% methylated cellulose aqueous solution is added to final volume.
2.4 for trying drug products for administration
The each test compound of male SD rat each three, fasting is administered after one night, and intravenous dosage is 5mg/kg, stomach-filling agent Measure 10mg/kg.
3. experimental implementation
Blood is taken through jugular puncture with rear 0.083-24h different time points and rat before administration, K2-EDTA is anticoagulant, from The heart takes blood plasma, and -70 DEG C of freezen protectives are until LC/MS/MS is analyzed.
4. pharmacokinetic data result
Note: A:IV (5mg/kg)；B:PO (10mg/kg)
The experimental results showed that two chiral isomers obtained after splitting are in Cmax, AUC and F% (biological utilisation Degree) difference of highly significant is shown, the oral AUC of the chipal compounds of one of configuration is more oral than its enantiomter AUC is higher by one times or more, and (embodiment 3 is relative to embodiment 2；Embodiment 11 is relative to embodiment 10；Embodiment 15 is relative to reality Apply example 14), the bioavilability of the chiral isomer of one of configuration is higher by than the bioavilability of its enantiomter 15% or more (embodiment 3 is relative to embodiment 2；Embodiment 11 is relative to embodiment 10；Embodiment 15 is relative to embodiment 14). Chipal compounds are compared with racemoid, and chipal compounds (3 compound of embodiment) are in Cmax, AUC and F% (biological utilisation Degree) etc. be significantly better than its racemoid (1 compound of embodiment).

Claims (11)

1. a kind of such as or mixtures thereof general formula I-A, I-B compound represented, its pharmaceutically acceptable salt, isomers, solvent Compound, polymorph, stable isotope derivatives or prodrug:
In formula,
R is selected from substituted or unsubstituted, unbranched or has a branch, saturated or unsaturated C1-10Alkyl or C3-12Naphthenic base, substitution Or unsubstituted aryl；Substituted or unsubstituted saturated or unsaturated heterocycle；-L1-L2, L1Selected from C substituted or unsubstituted1-10 Alkyl, L2Selected from aryl or heterocycle, hetero atom is selected from N, O, S or P in the heterocycle.
2. general formula I-A, I-B compound represented according to claim 1, its pharmaceutically acceptable salt, isomers or Its mixture, solvate, polymorph, stable isotope derivatives or prodrug, which is characterized in that R is selected from substitution or not Substituted C1-10Alkyl or alkylaryl, preferably substituted or unsubstituted C1-6Alkyl.
3. general formula I-A, I-B compound represented according to claim 1, its pharmaceutically acceptable salt, isomers or Its mixture, solvate, polymorph, stable isotope derivatives or prodrug, which is characterized in that R is selected from-L1-L2, L1 Selected from C substituted or unsubstituted1-6Alkyl, more preferable C1-4Alkyl, preferably L2Selected from aryl or heterocycle.
4. general formula I-A, I-B compound represented according to claim 1, its pharmaceutically acceptable salt, isomers or Its mixture, solvate, polymorph, stable isotope derivatives or prodrug, which is characterized in that R is selected from methyl.
5. general formula I-A, I-B compound represented according to claim 1, its pharmaceutically acceptable salt, isomers or Its mixture, solvate, polymorph, stable isotope derivatives or prodrug, which is characterized in that the compound tool Just like flowering structure:
6. it is a kind of prepare according to claim general formula I-A, I-B compound represented, its pharmaceutically acceptable salt, isomers or The method of its mixture, solvate, polymorph, stable isotope derivatives or prodrug, which is characterized in that the method Comprising steps of
3- quinuclidone under alkaline condition, reacts to obtain the general formula I-C compound of racemization with first aldehyde and alcohol, general formula I-C can lead to It crosses chiral column or chemical resolution method carries out chiral separation and obtains the general formula compound I-A and I-B of two single configurations, wherein R The definition of group is as defined in claim 1.
7. a kind of pharmaceutical composition, the pharmaceutical composition include a effective amount of general formula I-A according to claim 1, It is or mixtures thereof I-B compound represented, its pharmaceutically acceptable salt, isomers, solvate, polymorph, stable Isotope derivatives or prodrug and pharmaceutically acceptable carrier, diluent or excipient.
8. general formula I-A, I-B compound represented according to claim 1, its pharmaceutically acceptable salt, isomers or Its mixture, solvate, polymorph, stable isotope derivatives or prodrug or claim 7 described pharmaceutical composition Preparation can application in the drug by P53 mutation-related diseases for preventing, alleviating and/or treat.
9. application according to claim 8, it is characterised in that described to be selected from cancer, inflammation by P53 mutation-related diseases Property disease, autoimmune disease, cardiovascular disease, heart disease, virus infection.
10. application according to claim 9, it is characterised in that the cancer be selected from oophoroma, prostate cancer, myeloma, The cancer of the esophagus, gastric cancer, acute myeloid leukemia, chronic myelomonocytic leukemia, acute or chronic leukaemia.
11. general formula I-A, I-B compound represented according to claim 1, its pharmaceutically acceptable salt, isomers or Its mixture, solvate, polymorph, stable isotope derivatives or prodrug and another or a variety of anti-cancer agent in conjunction It uses, the anticancer agent preferred alkylating agent, platinum medicine, topoisomerase enzyme inhibitor, DNA/RNA synthetic inhibitor, DNA first Based transferase, liposome, alkaloid, antibody drug, hormone anticancer agent, proteasome inhibitor, hdac inhibitor, CDK kinases Inhibitor, VEGFR or EGFR inhibitor, m-TOR inhibitor, PI3K kinase inhibitor, B-Raf inhibitor, PARP inhibitor, c- Met kinase inhibitor, ALK kinase inhibitor, AKT inhibitor, ABL inhibitor, FLT3 inhibitor, PD-1 monoclonal antibody, PD-L1 are mono- It is anti-.
CN201710603967.2A 2017-07-21 2017-07-21 Chiral 3- quinuclidine ketone compounds, Preparation method and use Pending CN109280056A (en)

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