CN104860922A - Pyrimidine derivatives as anaplastic lymphoma kinase inhibitors - Google Patents

Pyrimidine derivatives as anaplastic lymphoma kinase inhibitors Download PDF

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Publication number
CN104860922A
CN104860922A CN201410062428.9A CN201410062428A CN104860922A CN 104860922 A CN104860922 A CN 104860922A CN 201410062428 A CN201410062428 A CN 201410062428A CN 104860922 A CN104860922 A CN 104860922A
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pyrimidine derivatives
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branched
branched alkyl
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王能辉
徐荣臻
谢枚强
干小仙
薛英汉
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Ningbo Wonder Pharmaceutical Technology Co Ltd
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Ningbo Wonder Pharmaceutical Technology Co Ltd
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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
    • A61K31/495—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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

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Abstract

The invention discloses pyrimidine derivatives as anaplastic lymphoma kinase inhibitors; the pyrimidine derivatives have a structure represented by the formula I, wherein in the formula, definitions of W, R1, R2, R3 and R4 are stated in the description and claims. The pyrimidine derivatives can be used as the anaplastic lymphoma kinase inhibitors and used for treatment of tumors, especially non-small cell lung cancer.

Description

As the pyrimidine derivatives of Nucleophosmin-anaplastic lymphoma kinase inhibitor
Technical field
The present invention relates to kinase inhibitor, be specifically related to a kind of pyrimidine derivatives as Nucleophosmin-anaplastic lymphoma kinase inhibitor.
Background technology
Nucleophosmin-anaplastic lymphoma kinase (anaplastic lymphoma kinase, ALK) fusion gene is the crucial carcinogenic factor of in part late period non-small cell lung cancer patient.Carcinogenic fusion gene can be detected in the non-small cell lung cancer patient of 2-7%, comprise echinoderms microtubule bindin 4(echinoderm microtubule-associated protein-like4, EML4) and Nucleophosmin-anaplastic lymphoma kinase (ALK).The undue expression of Nucleophosmin-anaplastic lymphoma kinase (ALK), variation can cause canceration.Therefore the inhibitor finding effective Nucleophosmin-anaplastic lymphoma kinase (ALK) becomes a kind of approach for the treatment of non-small cell lung cancer patient.
It is an effective target spot that gram azoles demonstrates Nucleophosmin-anaplastic lymphoma kinase (ALK) for the successful exploitation of Buddhist nun (Crizotinib).Because gram azoles replaces the low efficacy of Buddhist nun (Crizotinib) to impel the medicine found and have more high-drug-effect to treat non-small cell lung cancer.
Summary of the invention
The object of the present invention is to provide a kind of high-drug-effect, Nucleophosmin-anaplastic lymphoma kinase (ALK) inhibitor of highly selective.
A first aspect of the present invention, provides a kind of pyrimidine derivatives and pharmacy acceptable salt thereof, it is characterized in that, the structure of described pyrimidine derivatives is as shown in the formula shown in I:
In formula,
W is-NH-;
R 1for C 1-C 8straight or branched alkyl or the C replaced 1-C 8straight or branched alkyl;
R 2for C 1-C 8straight or branched alkyl, C 1-C 8the C of straight or branched alkoxyl group, replacement 1-C 8straight or branched alkyl or the C replaced 1-C 8straight or branched alkoxyl group; Or R 2for being selected from the group of lower group and connecting into ring with W: C 1-C 8straight or branched alkylidene group, C 1-C 8the C of straight or branched alkylene oxide group, replacement 1-C 8the C of straight or branched alkylidene group, replacement 1-C 8straight or branched alkylene oxide group;
R 3for H, F, Cl, Br, I, C 1-C 8straight or branched alkyl or the C replaced 1-C 8straight or branched alkyl;
R 4for-S (O 2) R 5,-S (O) R 5r 6,-P (O 2) R 5, or-P (O) R 5r 6, each R 5, each R 6independently selected from C 1-C 8the C of straight or branched alkyl, replacement 1-C 8straight or branched alkyl,
Wherein, each replacement refers to that the H on alkyl is selected from the substituting group replacement of lower group: F, Cl, Br, I,
In another preference, R 1for C 1-C 6straight or branched alkyl, or the C replaced 1-C 6straight or branched alkyl.
In another preference, R 2for the C that fluorine replaces 1-C 6straight or branched alkyl, or R 2for being selected from the group of lower group and connecting into ring with W: C 1-C 6the C that straight or branched alkylidene group, fluorine replace 1-C 6straight or branched alkylidene group.
In another preference, R 2for-CHF 2or-CF 2cH 3, or R 2for being selected from the group of lower group and connecting into ring with W: C 1-C 4the C that straight or branched alkylidene group, fluorine replace 1-C 4straight or branched alkylidene group.
In another preference, R 4for-S (O 2) R 5,-P (O) R 5r 6, each R 5, each R 6independently selected from C 1-C 4straight or branched alkyl.
In another preference, each R 5, each R 6independently selected from methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl or isobutyl-.
In another preference, described pyrimidine derivatives is selected from:
A second aspect of the present invention, provides the preparation method of the pyrimidine derivatives described in first aspect, comprises the following steps:
Formula II compound and formula III compound react the pyrimidine derivatives described in production I,
In formula, R is F, Cl, Br or I;
W, R 1, R 2, R 3, R 4definition as described in relation to the first aspect.
In another preference, R 1for C 1-C 6straight or branched alkyl, or the C that fluorine replaces 1-C 6straight or branched alkyl.
In another preference, R 2for-CHF 2, or-CF 2cH 3.
In another preference, R 3for-CH 3, or-CH 2cH 3.
In another preference, R 4for-S (O 2) R 5,-P (O) R 5r 6, each R 5, each R 6independently selected from C 1-C 4straight or branched alkyl.
In another preference, each R 5, each R 6independently selected from methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl or isobutyl-.
A third aspect of the present invention, provides the purposes of pyrimidine derivatives described in first aspect or its pharmacy acceptable salt, can be used as:
I () is as kinase inhibitor;
(ii) for the preparation of the medicine preventing and/or treating tumour; Or
(iii) for the preparation of kinase inhibitor.
A fourth aspect of the present invention, provides a kind of pharmaceutical composition, comprises:
(i) pyrimidine derivatives according to claim 1 or its pharmacy acceptable salt; With
(ii) pharmaceutically acceptable carrier.
Pyrimidine derivatives of the present invention and pharmacy acceptable salt thereof, can be used as Nucleophosmin-anaplastic lymphoma kinase (ALK) inhibitor, have high-drug-effect, highly selective, may be used for preventing and/or treating tumour, especially the tumour such as nonsmall-cell lung cancer.
Should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and can combining mutually between specifically described each technical characteristic in below (eg embodiment), thus form new or preferred technical scheme.As space is limited, tiredly no longer one by one to state at this.
Embodiment
Present inventor, through extensively and in depth studying, surprisingly develops a kind of novel structure such as formula the pyrimidine derivatives shown in I first, as Nucleophosmin-anaplastic lymphoma kinase inhibitor, has high-drug-effect and highly selective.On this basis, the present invention is completed.
Term
Nucleophosmin-anaplastic lymphoma kinase (ALK)
Nucleophosmin-anaplastic lymphoma kinase (ALK) is a kind of receptor type tyrosine kinase, and it is present in kinds of tumors extremely, closely related with tumor development, as primary cutaneous type, rhabdosarcoma, Inflammatory myofibroblastic tumor, NB.The anomaly pattern of ALK mainly comprises gene fusion, transgenation, gene amplification and protein expression to be increased.
Group
In context of the present invention, term " alkyl " represents saturated linear or branched chain hydrocarbon moiety, such as-CH 3or-CH (CH 3) 2.
In context of the present invention, term " alkylidene group " expression-C nh 2n-the linear or organic divalent functional groups of side chain, wherein n is 1-8, can be also 1-6 or 1-4, as methylene radical-CH 2-, ethylidene-CH 2cH 2-etc.
In context of the present invention, term " alkoxyl group " represents-O-(C1-8 alkyl) group, as-OCH 3,-OCH 2cH 3.
In context of the present invention, term " alkylene oxide group " represents-O-(C1-8 alkylidene group) group, as-OCH 2-,-OCH 2cH 2-or-OCH (CH 3) 2.
Unless otherwise indicated, alkyl as herein described, alkylidene group, alkoxyl group and alkylene oxide group comprise replacement with unsubstituted group simultaneously.Alkyl, alkylidene group, in alkoxyl group and alkylene oxide group, possible substituting group comprises, but be not limited to: C1-C10 alkyl, C2-C10 thiazolinyl, C2-C10 alkynyl, C3-C20 cycloalkyl, C3-C20 cycloalkenyl group, C1-C20 Heterocyclylalkyl, C1-C20 heterocycloalkenyl, C1-C10 alkoxyl group, aryl, heteroaryl, heteroaryloxy, amino, C1-C10 alkylamino, C1-C20 dialkyl amido, arylamino, ammonia diaryl base, C1-C10 alkylsulfamoyl group, ammonia aryl sulfonyl, C1-C10 alkyl imino, C1-C10 alkyl sulfobetaines imino-, aryl sulfo group imino-, hydroxyl, halogen, sulfydryl, C1-C10 alkylthio, C1-C10 alkyl sulphonyl, aryl sulfonyl, acyl amino, aminoacyl, aminothio acyl group, guanidine radicals, urea groups, cyano group, nitro, acyl group, Thioacyl, acyloxy, carboxyl and carboxylic acid ester groups.On the other hand, cycloalkyl, Heterocyclylalkyl, heterocycloalkenyl, aryl and heteroaryl also can condense mutually.
In the present invention, replace and refer to and to be replaced by one or more substituting group.
Term " thiazolinyl " represents the straight or branched hydrocarbyl portion comprising at least one double bond, such as-CH=CH-CH 3.Term " alkynyl " represents the straight or branched hydrocarbyl portion comprising at least one triple bond, such as-C ≡ C-CH 3.Term " cycloalkyl " represents saturated cyclic hydrocarbyl moiety, such as cyclohexyl.Term " Heterocyclylalkyl " represents the saturated circular part comprising at least one ring hetero atom (such as N, O or S), such as 4-THP trtrahydropyranyl.Term " aryl " represents the hydrocarbyl portion comprising one or more aromatic ring.The example of aryl moiety comprises phenyl (Ph), naphthyl, pyrenyl, anthryl and phenanthryl.Term " heteroaryl " expression comprises one or more part with the aromatic ring of at least one heteroatoms (such as N, O or S).The example of heteroaryl moieties comprises furyl, fluorenyl, pyrryl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidyl, quinazolyl, quinolyl, isoquinolyl and indyl.Term " amino " expression-NH 2,-NH-(C 1-6alkyl) or-N (C 1-6alkyl) 2.
Pharmacy acceptable salt of the present invention can be the salt that group positively charged in negatively charged ion and formula I is formed.Suitable negatively charged ion comprises chlorion, bromide anion, iodide ion, sulfate radical, nitrate radical, phosphate radical, citrate, methylsulphonic acid root, trifluoroacetic acid root, acetate moiety, malate, tosylate, tartrate anion, fumaric acid radical, glutamate, glucuronic acid root, lactate, glutarate and maleate.Similarly, salt can be formed by the electronegative group (such as carboxylate radical) on positively charged ion and formula I.Suitable positively charged ion comprises sodium ion, potassium ion, magnesium ion, calcium ion and ammonium ion, such as tetramethyl ammonium.In another preference, " pharmacy acceptable salt " refers to the salt with being selected from following acid formation: hydrofluoric acid, hydrochloric acid, Hydrogen bromide, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, methylsulfonic acid, Whitfield's ointment, trifluoromethanesulfonic acid, naphthene sulfonic acid, toxilic acid, citric acid, acetic acid, tartrate, succsinic acid, Herba Oxalidis Corniculatae acid, oxysuccinic acid, L-glutamic acid.
Pyrimidine derivatives and pharmacy acceptable salt thereof
The structure of pyrimidine derivatives of the present invention is as shown in the formula shown in I:
In formula,
W is-NH-;
R 1for C 1-C 8straight or branched alkyl or the C replaced 1-C 8straight or branched alkyl;
R 2for C 1-C 8straight or branched alkyl, C 1-C 8the C of straight or branched alkoxyl group, replacement 1-C 8straight or branched alkyl or the C replaced 1-C 8straight or branched alkoxyl group; Or R 2for being selected from the group of lower group and connecting into ring with W: C 1-C 8straight or branched alkylidene group, C 1-C 8the C of straight or branched alkylene oxide group, replacement 1-C 8the C of straight or branched alkylidene group, replacement 1-C 8straight or branched alkylene oxide group;
R 3for H, F, Cl, Br, I, C 1-C 8straight or branched alkyl or the C replaced 1-C 8straight or branched alkyl;
R 4for-S (O 2) R 5,-S (O) R 5r 6,-P (O 2) R 5, or-P (O) R 5r 6, each R 5, each R 6independently selected from C 1-C 8the C of straight or branched alkyl, replacement 1-C 8straight or branched alkyl,
Wherein, each replacement refers to that the H on alkyl is selected from the substituting group replacement of lower group: F, Cl, Br, I,
Described each replacement refers to and to be replaced by one or more substituting group.
In another preference, described each replacement refers to and to be replaced by 2-5 substituting group.
In another preference, R 3for H, F, Cl, Br, I, C 1-C 4straight or branched alkyl.
In another preference, R 3for methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl or isobutyl-.
In another preference, R 2for CF 2h or CF 2cH 3, or R 2for being selected from the group of lower group and connecting into ring with W: C 1-C 6the C of straight or branched alkylidene group, replacement 1-C 6straight or branched alkylidene group.
In another preference, R 1for C 1-C 6straight or branched alkyl, or the C replaced 1-C 6straight or branched alkyl.
In another preference, R 1for the C that fluorine replaces 1-C 6straight or branched alkyl.
In another preference, R 1for C 1-C 6straight or branched alkyl, or the C that fluorine replaces 1-C 6straight or branched alkyl
In another preference, R 1for-C (CH 3) 2, or-CF 2cH 3, or-CHF 2.
In another preference, R 2for the C that fluorine replaces 1-C 6straight or branched alkyl, or R 2for being selected from the group of lower group and connecting into ring with W: C 1-C 6the C that straight or branched alkylidene group, fluorine replace 1-C 6straight or branched alkylidene group.
In another preference, R 2for-CHF 2or-CF 2cH 3, or R 2for being selected from the group of lower group and connecting into ring with W: C 1-C 4the C that straight or branched alkylidene group, fluorine replace 1-C 4straight or branched alkylidene group.
In another preference, R 4for-S (O 2) R 5,-P (O) R 5r 6, each R 5, each R 6independently selected from C 1-C 4straight or branched alkyl.
In another preference, each R 5, each R 6independently selected from methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl or isobutyl-.
In another preference, described pharmacy acceptable salt is selected from: hydrofluoride, hydrochloride, hydrobromate, vitriol, phosphoric acid salt, mesylate, fluoroform sulphonate, benzene sulfonate, naphthalenesulfonate, acetate, trifluoroacetate, malate, oxalate, maleate, salicylate.
In another preference, described pyrimidine derivatives is selected from lower group:
Preparation method
The preparation method of pyrimidine derivatives of the present invention, comprises the following steps:
Formula II compound and formula III compound react the pyrimidine derivatives described in production I,
In formula, R is F, Cl, Br or I;
W, R 1, R 2, R 3, R 4definition as previously mentioned.
In another preference, R is Cl.
In another preference, R 1for C 1-C 6straight or branched alkyl, or the C that fluorine replaces 1-C 6straight or branched alkyl.
In another preference, R 2for-CHF 2, or-CF 2cH 3.
In another preference, R 3for-CH 3, or-CH 2cH 3.
In another preference, R 4for-S (O 2) R 5,-P (O) R 5r 6, each R 5, each R 6independently selected from C 1-C 4straight or branched alkyl.In another preference, each R 5, each R 6independently selected from methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl or isobutyl-.
In another preference, following route is adopted to prepare formula III compound:
In various, R, R ' independently selected from F, Cl, Br or I;
W, R 2, R 4definition as previously mentioned.
In another preference, R, R ' be Cl.
In another preference, R 2for-CHF 2, adopt following route to prepare pyrimidine derivatives:
Purposes
Pyrimidine derivatives of the present invention or its pharmacy acceptable salt, can be used as:
I () is as kinase inhibitor;
(ii) for the preparation of the medicine preventing and/or treating tumour; Or
(iii) for the preparation of kinase inhibitor.
In another preference, described tumour is selected from: liver cancer, lung cancer (comprising mediastinum cancer), oral epithelium cancer, nasopharyngeal carcinoma, thyroid carcinoma, esophagus cancer, lymphatic cancer, thoracic cavity cancer, digestive tract cancer, carcinoma of the pancreas, intestinal cancer, mammary cancer, ovarian cancer, uterus carcinoma, kidney, carcinoma of gallbladder, cholangiocarcinoma, nervus centralis cancer, carcinoma of testis, bladder cancer, prostate cancer, skin carcinoma, melanoma, meat cancer, the cancer of the brain, leukemia (leukemia), cervical cancer, glioma, cancer of the stomach or ascitic tumor.
In another preference, described tumour is selected from: nonsmall-cell lung cancer.
In another preference, described kinase inhibitor is Nucleophosmin-anaplastic lymphoma kinase inhibitor.
Pharmaceutical composition
The present invention also provides a kind of pharmaceutical composition, and described pharmaceutical composition comprises:
(i) pyrimidine derivatives of the present invention or its pharmacy acceptable salt; With
(ii) pharmaceutically acceptable carrier.
In another preference, be that the pyrimidine derivatives of 0.01%-99.95% or its pharmacy acceptable salt are as activeconstituents containing weight ratio in described composition.
This pharmaceutical composition is preferably that the pyrimidine derivatives of 0.1%-99.9% or its pharmacy acceptable salt are as activeconstituents containing weight ratio, preferably, containing weight ratio be the pyrimidine derivatives of 0.1%-99.5% or its pharmacy acceptable salt as activeconstituents, be more preferably the activeconstituents of 0.5%-95% containing weight ratio.
This pharmaceutical composition, pyrimidine derivatives of the present invention containing treatment significant quantity or its pharmacy acceptable salt, can be used as Nucleophosmin-anaplastic lymphoma kinase inhibitor, can be used as a kind of medicine preventing and/or treating tumour of efficient, highly selective, especially nonsmall-cell lung cancer.
" pharmaceutically acceptable carrier " refers to: one or more biocompatible solid or liquid filler or gelatinous mass, and they are suitable for people and use, and must have enough purity and enough low toxicity." consistency " to referred to herein as in composition each component energy and activeconstituents of the present invention and they between mutually admix, and the drug effect of not obvious reduction activeconstituents.Pharmaceutically acceptable carrier part example have cellulose and its derivates (as Xylo-Mucine, ethyl cellulose sodium, cellulose ethanoate etc.), gelatin, talcum, solid lubricant (as stearic acid, Magnesium Stearate), calcium sulfate, vegetables oil (as soya-bean oil, sesame oil, peanut oil, olive wet goods), polyvalent alcohol (as propylene glycol, glycerine, N.F,USP MANNITOL, sorbyl alcohol etc.), emulsifying agent (as ), wetting agent (as sodium lauryl sulphate), tinting material, seasonings, stablizer, antioxidant, sanitas, apirogen water etc.
Can by the mixture of pyrimidine derivatives of the present invention or the pharmaceutically acceptable carrier such as its pharmacy acceptable salt and pharmaceutically acceptable vehicle, thinner with the form oral administration of tablet, capsule, granule, powder or syrup or with the form non-oral administration of injection.Above-mentioned preparation is prepared by conventional pharmaceutical method.The example of available pharmaceutically acceptable carrier comprises vehicle, and (such as carbohydrate derivative is as lactose, sucrose, glucose, mannitol and Sorbitol Powder, starch derivative is as W-Gum, potato starch, dextrin and carboxymethyl starch, derivatived cellulose is as crystalline cellulose, hydroxypropylcellulose, carboxymethyl cellulose, calcium carboxymethylcellulose, Xylo-Mucine, gum arabic, dextran, silicate derivative is as Neusilin US2, phosphate derivative is as calcium phosphate, carbonate derivative is as calcium carbonate, sulfate-derivatives is as calcium sulfate etc.), tackiness agent (such as gelatin, polyvinylpyrrolidone and polyoxyethylene glycol), (such as derivatived cellulose is as Xylo-Mucine for disintegrating agent, polyvinylpyrrolidone), lubricant (such as talcum, calcium stearate, Magnesium Stearate, spermaceti, boric acid, Sodium Benzoate, leucine), stablizer (methyl p-hydroxybenzoate, propylparaben etc.), correctives (such as conventional sweeting agent, acidic flavoring agent and spices etc.), thinner and injection liquid solvent (such as water, ethanol and glycerine etc.).
When making pharmaceutical composition, that the pyrimidine derivatives of the present invention of safe and effective amount or its pharmacy acceptable salt are applied to Mammals, " safe and effective amount " refers to: the amount of activeconstituents is enough to obviously improve the state of an illness, and is unlikely to produce severe side effect.Wherein this safe and effective amount is usually at least about 1 micro-gram/day, and is in most of the cases no more than about 10 mg/kg body weight.Preferably, this dosage is about 1 micro-gram/day of-Yue 3 mg/kg body weight.Certainly, concrete dosage also should consider the factor such as route of administration, patient health situation, and these are all within skilled practitioners skill.Usually, pharmaceutical composition contains 1-2000mg activeconstituents/agent, more preferably, containing 10-200mg activeconstituents/agent.Preferably, described " potion " is a tablet.
In addition, pyrimidine derivatives of the present invention or its pharmacy acceptable salt can use by single medicine, also can with other medicines conbined usage.Preferred conbined usage comprises: with surgical operation conbined usage, with one or more Western medicine conbined usage, with herbal medicine conbined usage, with radiation treatment conbined usage.
The route of administration of pharmaceutical composition of the present invention is not particularly limited, comprising but be not limited to: oral administration, drug administration by injection, administration in knurl, drug delivery implant, intracavitary administration, anum administration, transdermal administration, interior external application; Preferred drug administration by injection comprises: intravenous injection, intramuscular injection, subcutaneous injection, administration in intracavitary administration, knurl.
The above-mentioned feature that the present invention mentions, or the feature that embodiment is mentioned can arbitrary combination.All features that this case specification sheets discloses can with any composition forms and use, each feature disclosed in specification sheets, anyly can be provided identical, alternative characteristics that is impartial or similar object replaces.Therefore apart from special instruction, the feature disclosed is only general example that is impartial or similar features.
Usefulness of the present invention is:
(1) the invention provides a kind of pyrimidine derivatives of novel texture as Nucleophosmin-anaplastic lymphoma kinase inhibitor;
(2) pyrimidine derivatives of the present invention has high-drug-effect and highly selective.
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usual conveniently condition is as people such as Sambrook, molecular cloning: laboratory manual (New York:Cold Spring Harbor Laboratory Press, 1989) condition described in, or according to the condition that manufacturer advises.Unless otherwise indicated, otherwise per-cent and number calculate by weight.
Unless otherwise defined, all specialties used in literary composition and scientific words and one skilled in the art the same meaning be familiar with.In addition, any method similar or impartial to described content and material all can be applicable in the inventive method.The use that better implementation method described in literary composition and material only present a demonstration.
Embodiment 1
The preparation of pyrimidine derivatives
Step 1
Be dissolved in 200ml THF by bromo-for 5-2,4,6-trichloropyrimidines (20g, 76mmol), this solution stirs 10 minutes at-30 DEG C.Isopropylmagnesium chloride (2M THF solution, 39ml, 78mmol) is slowly added drop-wise in above-mentioned solution, then stirs 30 minutes.Be added in above-mentioned solution by DMF (76mmol), then the temperature of solution gone back up to 0 DEG C lentamente, with saturated NH4Cl cancellation reaction, EtOAc extracts, and organic phase, with anhydrous sodium sulfate drying, is evaporated to dry solid.This solid Hexane washs, and obtains compound as white solid 2,4,6-trichloropyrimidine-5-aldehyde (14.5g, 68.5%)
Step 2
2,4,6-trichloropyrimidine-5-aldehyde (10g, 47.3mmol) is dissolved in 100mlCH2Cl2, is cooled to-20 DEG C.DAST (48mmol) is added drop-wise in solution lentamente, then stirs 1 hour.Pour this solution in the hydrochloric acid of cooling (1.0N, 100ml) lentamente.After organic phase anhydrous sodium sulfate drying, be evaporated to dry crude product (9.8g, 41.2mmol, 87%).
Step 3
By the crude product of above gained, 2,4,6-trichloropyrimidine-5-difluoromethyl (5g, 21.4mmol) be dissolved in ethyl acetate, under the condition of nitrogen, join platiniferous (Pd/C, 1090, in reaction flask 500mg), after this reaction flask vacuum deoxidation three times, stir in the environment of hydrogen balloon and spend the night.After filtering reacting liquid, concentrating under reduced pressure obtains crude product, obtains the chloro-5-difluoromethyl pyrimidin of solid 2,6-bis-(1.2g, 6mmol, 28%) through column chromatography purification (moving phase 90:10Hexane/EtOAc).
Step 4
By chloro-for 2,6-bis-5-difluoromethyl pyrimidin (1.2eq), intermediate A, salt of wormwood (4eq) is dissolved in DMF20ml, and reaction solution spends the night 60 DEG C of stirrings. after cool to room temperature, by the sedimentation and filtration in reaction, after drying, obtain crude product.Midbody product B (53%) is obtained through column chromatography purification (DCM:CH3OH=20:1).
Step 5
By intermediate B (1.0eq), intermediate C (1.2eq), chlorine (2-dicyclohexylphosphino-2', 6'-bis-I-propoxy--1,1'-biphenyl) [2-(2-amino-ethyl phenyl)] palladium (II), methyl tertiary butyl ether (0.01eq), Pd (OAc) 2(0.05eq) and CsCO 3(3eq) be dissolved in 10ml THF, reaction solution is with after nitrogen deoxidation 30min, and in the environment of nitrogen, 150 DEG C are refluxed six hours, and by reacting liquid filtering, after washing, after organic phase concentrating under reduced pressure, chromatographic separation purifying obtains final product (21%).
Embodiment 2
The preparation of pyrimidine derivatives
Step 1
By chloro-for 2,6-bis-5-difluoromethyl pyrimidin (1.2eq), intermediate D, salt of wormwood (4eq) is dissolved in DMF20ml, and reaction solution spends the night 60 DEG C of stirrings.After cool to room temperature, by the sedimentation and filtration in reaction, after drying, obtain crude product.Midbody product E (43%) is obtained through column chromatography purification (DCM:CH3OH=30:1).
Step 2
By intermediate E (1.0eq), intermediate C (1.2eq), chlorine (2-dicyclohexylphosphino-2', 6'-bis-I-propoxy--1,1'-biphenyl) [2-(2-amino-ethyl phenyl)] palladium (II), methyl tertiary butyl ether (0.01eq), Pd (OAc) 2(0.05eq) and CsCO 3(3eq) be dissolved in 10ml THF, reaction solution is with after nitrogen deoxidation 30min, and in the environment of nitrogen, 150 DEG C are refluxed six hours, and by reacting liquid filtering, after washing, after organic phase concentrating under reduced pressure, chromatographic separation purifying obtains final product (32%).
Embodiment 3
The preparation of pyrimidine derivatives
By intermediate B (1.0eq), intermediate F (1.2eq), chlorine (2-dicyclohexylphosphino-2', 6'-bis-I-propoxy--1,1'-biphenyl) [2-(2-amino-ethyl phenyl)] palladium (II), methyl tertiary butyl ether (0.01eq), Pd (OAc) 2(0.05eq) and CsCO 3(3eq) be dissolved in 10ml THF, reaction solution is with after nitrogen deoxidation 30min, and in the environment of nitrogen, 150 DEG C are refluxed six hours, and by reacting liquid filtering, after washing, after organic phase concentrating under reduced pressure, chromatographic separation purifying obtains final product (45%).
Embodiment 4
The preparation of pyrimidine derivatives
By intermediate E (1.0eq), intermediate F (1.2eq), chlorine (2-dicyclohexylphosphino-2', 6'-bis-I-propoxy--1,1'-biphenyl) [2-(2-amino-ethyl phenyl)] palladium (II), methyl tertiary butyl ether (0.01eq), Pd (OAc) 2(0.05eq) and CsCO 3(3eq) be dissolved in 10ml THF, reaction solution is with after nitrogen deoxidation 30min, and in the environment of nitrogen, 150 DEG C are refluxed six hours, and by reacting liquid filtering, after washing, after organic phase concentrating under reduced pressure, chromatographic separation purifying obtains final product (45%)
Embodiment 5
The preparation of pyrimidine derivatives
Adopt the method similar to embodiment 2 to prepare the pyrimidine derivatives of the present embodiment, reaction scheme is as follows.
Embodiment 6
The preparation of pyrimidine derivatives
Adopt the method similar to embodiment 2 to prepare the pyrimidine derivatives of the present embodiment, reaction scheme is as follows.
Embodiment 7
The preparation of pyrimidine derivatives
Adopt the method similar to embodiment 2 to prepare the pyrimidine derivatives of the present embodiment, reaction scheme is as follows.
Embodiment 8
The preparation of pyrimidine derivatives
Adopt the method similar to embodiment 1 to prepare the pyrimidine derivatives of the present embodiment, reaction scheme is as follows.
Embodiment 9
The preparation of pyrimidine derivatives
Adopt the method similar to embodiment 1 to prepare the pyrimidine derivatives of the present embodiment, reaction scheme is as follows.
This area ordinary method is adopted to detect, result shows that pyrimidine derivatives prepared by embodiment 1-9 can be used for suppressing the growth of the tumour cells such as liver cancer, lung cancer, lymphatic cancer, mammary cancer, ovarian cancer, cancer of the stomach, especially the growth of non-small cell lung cancer cell can be suppressed, can be used as Nucleophosmin-anaplastic lymphoma kinase inhibitor, for preventing and/or treating tumour, and there is high-drug-effect, highly selective.
The all documents mentioned in the present invention are quoted as a reference all in this application, are just quoted separately as a reference as each section of document.In addition should be understood that those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.

Claims (10)

1. pyrimidine derivatives and a pharmacy acceptable salt thereof, is characterized in that, the structure of described pyrimidine derivatives is as shown in the formula shown in I:
In formula,
W is-NH-;
R 1for C 1-C 8straight or branched alkyl or the C replaced 1-C 8straight or branched alkyl;
R 2for C 1-C 8straight or branched alkyl, C 1-C 8the C of straight or branched alkoxyl group, replacement 1-C 8straight or branched alkyl or the C replaced 1-C 8straight or branched alkoxyl group; Or R 2for being selected from the group of lower group and connecting into ring with W: C 1-C 8straight or branched alkylidene group, C 1-C 8the C of straight or branched alkylene oxide group, replacement 1-C 8the C of straight or branched alkylidene group, replacement 1-C 8straight or branched alkylene oxide group;
R 3for H, F, Cl, Br, I, C 1-C 8straight or branched alkyl or the C replaced 1-C 8straight or branched alkyl;
R 4for-S (O 2) R 5,-S (O) R 5r 6,-P (O 2) R 5, or-P (O) R 5r 6, each R 5, each R 6independently selected from C 1-C 8the C of straight or branched alkyl, replacement 1-C 8straight or branched alkyl,
Wherein, each replacement refers to that the H on alkyl is selected from the substituting group replacement of lower group: F, Cl, Br, I.
2. pyrimidine derivatives as claimed in claim 1, is characterized in that, R 1for C 1-C 6straight or branched alkyl, or the C replaced 1-C 6straight or branched alkyl.
3. pyrimidine derivatives as claimed in claim 1, is characterized in that, R 2for the C that fluorine replaces 1-C 6straight or branched alkyl, or R 2for being selected from the group of lower group and connecting into ring with W: C 1-C 6the C that straight or branched alkylidene group, fluorine replace 1-C 6straight or branched alkylidene group.
4. pyrimidine derivatives as claimed in claim 1, is characterized in that, R 2for-CHF 2or-CF 2cH 3, or R 2for being selected from the group of lower group and connecting into ring with W: C 1-C 4the C that straight or branched alkylidene group, fluorine replace 1-C 4straight or branched alkylidene group.
5. pyrimidine derivatives as claimed in claim 1, is characterized in that, R 4for-S (O 2) R 5,-P (O) R 5r 6, each R 5, each R 6independently selected from C 1-C 4straight or branched alkyl.
6. pyrimidine derivatives as claimed in claim 5, is characterized in that, each R 5, each R 6independently selected from methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl or isobutyl-.
7. pyrimidine derivatives as claimed in claim 1, it is characterized in that, described pyrimidine derivatives is selected from:
8. the preparation method of pyrimidine derivatives as claimed in claim 1, is characterized in that, comprise the following steps:
Formula II compound and formula III compound react the pyrimidine derivatives described in production I,
In formula, R is F, Cl, Br or I;
W, R 1, R 2, R 3, R 4definition as claimed in claim 1.
9. the purposes of pyrimidine derivatives as claimed in claim 1 or its pharmacy acceptable salt, is characterized in that; I () is as kinase inhibitor; (ii) for the preparation of the medicine preventing and/or treating tumour; Or (iii) is for the preparation of kinase inhibitor.
10. a pharmaceutical composition, is characterized in that, described pharmaceutical composition comprises:
(i) pyrimidine derivatives according to claim 1 or its pharmacy acceptable salt; With
(ii) pharmaceutically acceptable carrier.
CN201410062428.9A 2014-02-24 2014-02-24 Pyrimidine derivatives as anaplastic lymphoma kinase inhibitors Pending CN104860922A (en)

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WO2016127949A1 (en) * 2015-02-15 2016-08-18 宁波文达医药科技有限公司 Pyrimidine derivative as inhibitor for t790 mutation
WO2017076355A1 (en) * 2015-11-05 2017-05-11 湖北生物医药产业技术研究院有限公司 Pyrimidine derivative and use thereof
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WO2016127949A1 (en) * 2015-02-15 2016-08-18 宁波文达医药科技有限公司 Pyrimidine derivative as inhibitor for t790 mutation
WO2017076355A1 (en) * 2015-11-05 2017-05-11 湖北生物医药产业技术研究院有限公司 Pyrimidine derivative and use thereof
JP2018532759A (en) * 2015-11-05 2018-11-08 湖北生物医薬産業技術研究院有限公司Ｈｕｂｅｉ Ｂｉｏ−Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｉｎｄｕｓｔｒｉａｌ Ｔｅｃｈｎｏｌｏｇｉｃａｌ Ｉｎｓｔｉｔｕｔｅ Ｉｎｃ． Pyrimidine derivatives and uses thereof
US10695347B2 (en) 2015-11-05 2020-06-30 Hubei Bio-Pharmaceutical Industrial Technological Institute, Inc. Pyrimidine derivative and use thereof
CN109369721A (en) * 2017-12-21 2019-02-22 深圳市塔吉瑞生物医药有限公司 For inhibiting the aryl phosphorous oxides of kinase activity
CN109369721B (en) * 2017-12-21 2024-05-14 深圳市塔吉瑞生物医药有限公司 Aryl phosphorus oxides for inhibiting kinase activity
WO2020147838A1 (en) * 2019-01-18 2020-07-23 正大天晴药业集团股份有限公司 Salt of egfr inhibitor, crystal form, and preparation method therefor
CN113260613A (en) * 2019-01-18 2021-08-13 正大天晴药业集团股份有限公司 Salts and crystal forms of EGFR inhibitor and preparation method thereof
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CN110305140A (en) * 2019-07-30 2019-10-08 上海勋和医药科技有限公司 Pyrrolin miazines selectivity JAK2 inhibitor

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