WO2018018986A1 - 二苯氨基嘧啶及三嗪化合物、其药用组合物及用途 - Google Patents
二苯氨基嘧啶及三嗪化合物、其药用组合物及用途 Download PDFInfo
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- WO2018018986A1 WO2018018986A1 PCT/CN2017/083058 CN2017083058W WO2018018986A1 WO 2018018986 A1 WO2018018986 A1 WO 2018018986A1 CN 2017083058 W CN2017083058 W CN 2017083058W WO 2018018986 A1 WO2018018986 A1 WO 2018018986A1
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- Prior art keywords
- group
- compound
- phenyl
- diphenylaminopyrimidine
- hydrogen
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Classifications
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
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- C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
- C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
- C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
- C07D251/16—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom
- C07D251/18—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines
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- 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
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- 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
- C07D401/14—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 three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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- 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
- C07F9/65583—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 each of the hetero rings containing nitrogen as ring hetero atom
Definitions
- the invention relates to the field of biomedicine, in particular to a diphenylaminopyrimidine and triazine compound, a pharmaceutical composition thereof and use thereof.
- Anaplastic lymphoma kinase is a member of the insulin receptor tyrosine kinase superfamily. At present, more than twenty ALK fusion proteins produced by different chromosomal rearrangements have been discovered. Including the onset of large cell lymphoma, diffuse large B-cell lymphoma, inflammatory myofibroblastic tumor, neuroblastoma, and the like. ALK fusion proteins play a fundamental role in the development of approximately 5-10% of non-small cell lung cancers. Mutation and overexpression of ALK fusion proteins are associated with a variety of diseases, which are involved in complex signal transduction, which in turn affects cell proliferation, differentiation and apoptosis. ALK kinase inhibitors can be used to treat cancer and autoimmune diseases.
- the second-generation ALK kinase inhibitors are selective ALK kinase inhibitors for the treatment of cancer and cell proliferative disorders and other related diseases. Ceritinib and Alectinib have been approved for treatment of Crizotinib. ALK-specific non-small cell lung cancer patients. In addition, studies using ALK selective inhibitors to treat leukemias and lymphomas are also underway.
- a potentinib-related diphenylaminopyrimidine compound is disclosed in WO2004080980A1 and WO2008073687A2, and an Alectinib-related compound is disclosed in WO2010143664A1.
- ALK kinase inhibitors have alleviated the treatment of ALK-specific lung cancer and its drug resistance to some extent, there are still problems of insufficient activity and efficacy, which makes these drugs use relatively large doses.
- Crizotinib requires 500 mg per day, while Alectinib and Ceritinib use more than 750-1200 mg per day, indicating that these drugs are far from satisfactory in terms of the effectiveness of the treatment.
- WO2014173291A1 discloses a series of deuterated diaminopyrimidine compounds to improve the efficacy and drug-forming properties of Ceritinib, but the related pharmacological effects and drug-forming properties are not significantly improved.
- ALK kinase inhibitors that have been discovered, in addition to the existence of further improvement in drug efficacy, there are still many problems such as poor drug-forming properties, prominent drug resistance and obvious side effects, and thus it has been found to have specific inhibitory effects, low dosage, and more New compounds with good drug resistance and resistance to resistance, as well as low toxicity, are very challenging and necessary.
- the present invention provides a diphenylaminopyrimidine and a triazine compound, or a pharmaceutically acceptable salt, stereoisomer, hydrate or solvate thereof, use thereof, and pharmaceutical composition.
- the diphenylaminopyrimidine and triazine compound, or a pharmaceutically acceptable salt, stereoisomer, hydrate or solvate thereof have better pharmacodynamics and pharmacokinetic properties, and can effectively inhibit ALK kinase active.
- the invention provides a diphenylaminopyrimidine and triazine compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, hydrate or solvate thereof:
- A is C or N
- X, Y are independently selected from hydrogen, halogen, cyano, trifluoromethyl, alkoxy, alkyl, arylcyclo, alkenyl, alkynyl or nitro; or, X and Y are attached to them ( The C, or C and N) atoms together form a benzene ring or an aromatic heterocyclic ring containing one or more of oxygen, sulfur and nitrogen heteroatoms;
- R 1 is or
- R 2 is CD 3 or CD 2 CD 3 ;
- R 3 is selected from or
- R 4 is selected from the group consisting of hydrogen, methyl, trifluoromethyl, cyano or halogen;
- R 5 is selected from the group consisting of hydrogen, alkyl, substituted and unsubstituted phenyl, allyl or propargyl;
- R 6 and R 7 are independently selected from hydrogen, alkyl, substituted and unsubstituted phenyl, allyl, propargyl; or R 6 and R 7 together with the nitrogen (N) atom to which they are attached Or an unsubstituted heterocycloalkyl group which contains one or more of oxygen, sulfur, nitrogen, sulfoxide group and sulfone group.
- the aromatic heterocyclic ring is preferably acridine, carbazole, porphyrin, quinoxaline, pyrazole, hydrazine, benzotriazole, furan, thiophene, benzothiophene, benzofuran, quinoline, isoquinoline.
- Heterocycloalkyl is preferably oxazoline, oxocyclobutyl, pyranyl, tetrahydropyranyl, azetidinyl, 1,4-dioxyl, hexahydroazetyl, piperazinyl.
- the alkyl group is preferably a C1-C10 alkyl group
- the alkenyl group is preferably a C2-C12 alkenyl group, more preferably a C2-C4 vinyl group, and further preferably a vinyl group.
- the alkynyl group is preferably a C2-C12 alkynyl group, more preferably a C2-C4 alkynyl group, further preferably an ethynyl group.
- R 1 is R 2 is CD 3 , X is a halogen, and Y is hydrogen.
- the diphenylaminopyrimidine and the triazine compound are specifically any of the following compounds:
- the present invention provides a process for the preparation of a diphenylaminopyrimidine and a triazine compound of the above formula I, which comprises the steps of: deprotecting compound II to obtain a diphenyl group as shown in formula I. Pyrimidine and triazine compounds;
- the preparation method of the diphenylpyrimidine and triazine compound represented by Formula I further includes the following:
- PG is a protecting group and may be Boc (tert-butoxycarbonyl), CBz (benzyloxycarbonyl) or Troc (trichloroethoxycarbonyl), preferably Boc (tert-butoxycarbonyl).
- the method for preparing a diphenylpyrimidine and a triazine compound as shown in Formula I further comprises the steps of: coupling a compound V with a compound VI to obtain a compound III;
- A, X, Y, R 1 , R 2 , R 3 and R 4 are as defined above; the coupling can be carried out using conventional methods and conditions for such reactions in the art.
- the method for producing a diphenylpyrimidine and a triazine compound of the formula I further comprises the step of: protecting the amino group in the R 3 group of the compound VII, Obtaining the compound IV;
- R 1 , R 2 , R 3 and R 4 are as defined above;
- PG is a protecting group which may be Boc (tert-butoxycarbonyl), CBz (benzyloxycarbonyl) or Troc (trichloroethoxycarbonyl)
- Boc tert-butoxycarbonyl
- the protection reaction can be carried out using conventional methods and conditions for such reactions in the art.
- the preparation method of the diphenylpyrimidine and triazine compound represented by Formula I further includes the steps of: subjecting the nitro group of Compound VIII and the pyridyl group of R 3 ' Reduction reaction to obtain compound VII;
- R 1 , R 2 , R 3 , R 3 ' and R 4 are as defined above; the reduction reaction may employ conventional methods and conditions for such reactions in the art.
- the preparation method of the diphenylpyrimidine and triazine compound represented by Formula I further includes the following steps: subjecting Compound IX and Compound X to Suzuki Coupling reaction to obtain compound VIII;
- R 1 , R 2 , R 3 ' and R 4 are as defined above; the Suzuki coupling reaction may employ conventional methods and conditions for such reactions in the art.
- the preparation method of the diphenylpyrimidine and triazine compound of the formula I further comprises the following steps: the compound XI is subjected to a substitution reaction to obtain a compound IX;
- R 1 , R 2 and R 4 are as defined above; the reduction reaction may employ conventional methods and conditions for such reactions in the art.
- the method for producing a diphenylpyrimidine and a triazine compound of the formula I further comprises the step of: subjecting the nitro group of the compound VIII to Reduction can be carried out to obtain the compound IV.
- alkyl is a branched or straight-chain saturated aliphatic hydrocarbon group having the specified number of carbon atoms; as defined in “C1-C10 alkyl” as being included in a linear or branched structure. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atom groups.
- C1-C10 alkyl specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, decyl And ⁇ .
- alkoxy means a group formed by linking an alkyl group to an oxygen atom, that is, "RO-", and R is an alkyl group.
- cycloalkyl means an all-carbon monocyclic or polycyclic group, preferably 1 to 3 cyclic cycloalkyl groups formed by 3 to 20 carbons, more preferably 3 to 10 carbons, for example: Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecane or cyclododecyl.
- heterocycloalkyl refers to 4 comprising from 1 to 4 heteroatoms such as one or more of nitrogen, oxygen and sulfur.
- any heterocycloalkyl ring can be fused to a cycloalkyl, aryl, heteroaryl or heterocycloalkyl ring.
- Heterocycloalkyl groups within the scope of this definition include, but are not limited to, oxazoline, oxocyclobutyl, pyranyl, tetrahydropyranyl, azetidinyl, 1,4-dioxyl, Hexahydropyrazine, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrofuranyl, dihydroimidazolyl, indanyl, dihydroisoxazole , dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrogen Tetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydr
- alkenyl means a straight-chain, branched or cyclic non-aromatic hydrocarbon group containing a specified number of carbon atoms and at least one carbon-carbon double bond. Preferably there is one carbon-carbon double bond and up to four non-aromatic carbon-carbon double bonds may be present.
- C2-C12 alkenyl means an alkenyl group having 2 to 12 carbon atoms.
- the "C2-C4" alkenyl group means an alkenyl group having 2 to 4 carbon atoms, and includes a vinyl group, a propenyl group, a 2-methyl-propenyl group, a 1-butenyl group, and a 2-butenyl group.
- the linear, branched or cyclic moiety of the alkenyl group may contain a double bond.
- alkynyl means a straight-chain, branched or cyclic hydrocarbon group containing a specified number of carbon atoms and at least one carbon-carbon triple bond. There may be up to three carbon-carbon triple bonds.
- C2-C12 alkynyl group means an alkynyl group having 2 to 12 carbon atoms.
- C2-C4 alkynyl group means an alkynyl group having 2 to 4 carbon atoms, and includes an ethynyl group, a propynyl group, a 1-butynyl group, a 2-butynyl group and the like.
- aromatic ring means any stable monocyclic or bicyclic carbon ring which may be up to 7 atoms, at least one of which is an aromatic ring.
- aromatic ring group include a phenyl group, a naphthyl group, a tetrahydronaphthyl group, a 2,3-indanyl group, a biphenyl group, a phenanthryl group, an anthracenyl group or an acenaphthyl group. It will be understood that in the case where the aryl substituent is a bicyclic substituent and one of the rings is a non-aromatic ring, the linkage is carried out through an aromatic ring.
- aromatic heterocyclic ring means a stable monocyclic or bicyclic ring which may be up to 7 atoms, wherein at least one ring is an aromatic ring and contains 1 to 4 hetero atoms selected from O, N and S;
- rings include, but are not limited to, acridine, carbazole, porphyrin, quinoxaline, pyrazole, indole, benzotriazole, furan, thiophene, benzothiophene, benzofuran, quinoline, Isoquinoline, oxazole, isoxazole, hydrazine, pyrazine, pyridazine, pyridine, pyrimidine, pyrrole and tetrahydroquinoline.
- aromatic heterocycle is also understood to include any nitrogen-containing heteroaryl N-oxide derivative.
- heterocyclic aryl substituent is a bicyclic substituent and one ring is a non-aromatic ring or does not contain a hetero atom, it is understood that the linkage is carried out by an aromatic ring or by a hetero atom comprising a ring, respectively.
- a "Cx1-Cy1" alkyl group (x1 and y1 are integers), a cycloalkyl group, a heterocycloalkyl group, an aryl group and a heteroaryl group such as "C1-12 alkyl group" having a carbon number range are determined. All represent a C1-12 alkyl group which does not contain a substituent.
- halogen means fluorine, chlorine, bromine or iodine.
- provided herein are methods of making diphenylaminopyrimidines and triazine derivatives as shown in Formula I, and methods of use thereof.
- the compounds described herein can be synthesized using the schemes synthesized below, and the target compounds can be synthesized by selecting appropriate starting materials using methods analogous to those described below.
- the general methods of preparing the compounds disclosed herein can be derived from reactions known in the art, and the reactions can be modified to synthesize the target compound molecules by reagents and conditions deemed appropriate by those skilled in the art.
- the following synthesis methods can be used as a basic guide.
- reaction product can be post-treated (isolated and purified) using conventional techniques, including but not limited to For filtration, distillation, crystallization, chromatography and other methods. These products can be characterized using conventional analytical methods, including physical constants and map data (m.p, HPLC, LC-MS, NMR, optical rotation, etc.).
- the compounds described herein can be prepared as a single isomer using the synthetic methods described herein.
- the invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of any of the invention, or a pharmaceutically acceptable salt, stereoisomer, hydrate or solvate thereof, and one or more pharmaceuticals An acceptable carrier or excipient.
- the pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers including excipients and excipients which facilitate processing the active compound into a pharmaceutically acceptable formulation.
- the appropriate formulation will depend on the route of administration chosen. Any of the well-known techniques, carriers and excipients can be suitably employed and as understood in the art.
- the pharmaceutical composition of the present invention refers to a mixture of any one of the compounds of the examples described herein with other chemical components, such as a carrier, a stabilizer, an antioxidant, a disintegrant, a diluent, a dispersing agent, a filler, and a correction. Flavoring agents, suspending agents, glidants, solubilizers, surfactants, wetting agents, thickeners and/or excipients.
- the pharmaceutical composition facilitates administration of the compound to an organism.
- a therapeutically effective amount of a compound described herein is administered to a mammal having a disease, disorder or condition to be treated, in a pharmaceutical composition.
- the mammal is a human.
- the therapeutically effective amount can vary widely, depending on the severity of the disease, the age and relative health of the subject, the efficacy of the compound employed, and the like.
- the compounds may be used alone or in combination with one or more therapeutic agents that are components of the mixture.
- the pharmaceutical composition will comprise at least one compound of any of the compounds described herein as the active ingredient in the form of the free acid or the free base or as the active ingredient in the form of a pharmaceutically acceptable salt.
- the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), and active metabolites of these compounds having the same type of activity.
- the compounds may exist as tautomers. All tautomers are included within the scope of the compounds provided herein.
- the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. Solvate forms of the compounds provided herein are also considered to be disclosed herein.
- the present invention provides a pharmaceutical preparation comprising the above diphenylaminopyrimidine and a triazine compound, or a pharmaceutically acceptable salt, stereoisomer, hydrate or solvate thereof as an effective pharmaceutical ingredient.
- the pharmaceutical preparations described herein can be administered to a subject by a variety of routes of administration including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical , rectal or transdermal routes of administration.
- compositions described herein include, but are not limited to, aqueous dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, instant formulations, tablets , capsules, pills, sustained release preparations, extended release preparations, pulsation Release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.
- compositions for oral administration can be obtained by mixing one or more solid excipients with one or more of the compounds described herein, optionally grinding the resulting mixture, if necessary, after adding suitable excipients The mixture is granulated to obtain a tablet or tablet core.
- suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol, and the like; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, and western yellow.
- Silicone methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, etc.; surfactants such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.
- PVP polyvinylpyrrolidone
- a disintegrating agent such as cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate may be added.
- compositions which can be used orally include push-in capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol.
- the push-in capsules can contain the active ingredient in admixture in a filler such as lactose, a binder such as a starch and/or a lubricant such as talc or magnesium stearate, and optionally a stabilizer.
- the active compound can be dissolved or suspended in a suitable liquid, such as a fatty oil, liquid paraffin or liquid polyethylene glycol.
- a stabilizer may be added. All formulations for oral administration should be in a form suitable for such administration.
- the solid dosage forms disclosed herein may be in the form of tablets (including suspension tablets, instant tablets, chew disintegrating tablets, fast disintegrating tablets, effervescent tablets or caplets), Pills, powders (including aseptically packaged powders, non-essential powders or effervescent powders), capsules (including soft capsules or hard capsules, such as capsules made from animal-derived gelatin or capsules made from plant-derived HPMC) Or "dispersed capsules”), solid dispersions, solid solutions, bioerodible formulations, controlled release formulations, pulsatile release dosage forms, multiparticulate dosage forms, pellets, granules or aerosols.
- the pharmaceutical formulation is in powder form.
- the pharmaceutical formulation is in the form of a tablet, including but not limited to a fast dissolving tablet.
- the pharmaceutical preparations described herein can be administered as a single capsule or in a multi-capsule dosage form. In some embodiments, the pharmaceutical formulation is administered in two, or three, or four capsules or tablets.
- the pharmaceutical composition will comprise a formulation of at least one compound of any of the compounds described herein, suitable for intramuscular, subcutaneous or intravenous injection, and may include physiologically acceptable sterile water or non-aqueous solutions, dispersions. , suspensions or emulsions, and sterile powders for reconstituting sterile injectable solutions or dispersions.
- suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, cremophor, etc.), suitable mixtures thereof, vegetable oils (eg Olive oil) and organic esters for injection such as ethyl oleate.
- Appropriate fluidity can be maintained, for example by the use of a coating such as lecithin; by the maintenance of the required particle size; and by the use of surfactants.
- Formulations suitable for subcutaneous injection may also contain additives such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of microbial growth can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like.
- An isotonic agent such as sugar, sodium chloride or the like may also be included as needed.
- Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of delayed absorption agents such as aluminum monostearate and gelatin.
- the invention also relates to various pharmaceutical compositions known in the pharmaceutical arts for use in intraocular, intranasal and intra-oral delivery.
- the pharmaceutical formulation comprises an aqueous ophthalmic solution of the active compound, which may be present in a water soluble form such as an eye drop, or as a gellan gum or hydrogel; an ophthalmic ointment; an ophthalmic suspension, such as a microparticle, suspended in Small polymeric particles comprising a drug, a fat-soluble formulation, and microspheres in a liquid carrier medium; and an ophthalmic intercalator.
- these suitable pharmaceutical preparations are most often and preferably manufactured as sterile, isotonic and buffered preparations.
- compositions also include drops and sprays which often mimic nasal secretions in a number of ways to ensure maintenance of normal ciliary action.
- suitable formulations are most often and preferably isotonic, are lightly buffered to maintain a pH of 5.5 to 6.5, and most often and preferably include antimicrobial preservatives and appropriate drugs. stabilizer.
- Pharmaceutical formulations for intra-oral delivery include suspensions and ointments for topical application in the ear. Common solvents for these otic preparations include glycerin and water.
- the present invention also relates to any one of the compounds of any one of the compounds, or a pharmaceutically acceptable salt, stereoisomer, hydrate or solvate thereof, which can be administered orally, parenterally (intravenously, intramuscularly, subcutaneously) Etc., administered to a mammal, such as a human, via pulmonary, topical, dermal, and the like.
- the human dose of the compounds of the invention may range from about 0.1 mg to about 1000 mg.
- the present invention provides the use of any of the compounds, or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, active metabolite, and prodrug thereof, for the preparation of a medicament, which can be administered separately
- the drug, or in combination with other therapeutic agents is a drug for cancer, cardiovascular disease, infection, inflammation, immune disease, cell proliferative disease, organ transplantation, viral disease or metabolic disease.
- Combination drugs include, but are not limited to, doxorubicin, dactinomycin, bleomycin, vinblastine, cisplatin, acevicin; arubicin; apodazole hydrochloride; acronin; Aldileukin; hexamethylene melamine; ampomycin; aramid acetate; aziridine; ampicillin; anastrozole; acitretin; asparaginase; triamcinol; azacitidine Azatto; azamycin; bamastat; benzozide; bicalutamide; chlorinated hydrochloride; dimethyl sulfamate; diazepam; bleomycin sulfate; Buquina sodium; bromopyrimidine; busulfan; actinomycin C; carrazine; calamine; carbemide; carboplatin; carmustine; carbofuran hydrochloride; New; Westfinoco; chlorambucil; sir
- the invention further relates to the use of any of the compounds, or a pharmaceutically acceptable salt, stereoisomer, hydrate or solvate thereof, for the manufacture of a medicament, which is an ALK tyrosine kinase inhibitor, or for prevention Or treating a disease, disorder, or condition that benefits from inhibition of ALK tyrosine kinase activity.
- a medicament for treating and/or preventing a disease in a mammal, including a human, with a compound for inhibiting anaplastic lymphoma kinase (ALK) activity or for treating a disease that benefits from inhibition of anaplastic lymphoma kinase (ALK) activity, The use of a condition or condition.
- examples of anaplastic lymphoma kinase (ALK) mediated diseases or disease states include, but are not limited to, cancer, cell-value-added diseases, inflammation, infection, immune diseases, organ transplants, viral diseases, Cardiovascular disease or metabolic disease.
- ALK anaplastic lymphoma kinase
- the compounds of the invention are useful in the treatment of anaplastic lymphoma kinase (ALK) mediated diseases or disease states including cancers But not limited to head cancer, thyroid cancer, neck cancer, eye cancer, skin cancer, oral cancer, throat cancer, esophageal cancer, chest cancer, bone cancer, blood cancer, bone marrow cancer, lung cancer, head and neck cancer, colon cancer, sigmoid cancer , rectal cancer, colon cancer, nasopharyngeal cancer, stomach cancer, prostate cancer, breast cancer, ovarian cancer, uterine cancer, kidney cancer, liver cancer, pancreatic cancer, bladder cancer, brain cancer, colon cancer, heart cancer, adrenal cancer, subcutaneous tissue Cancer, lymph node cancer, lymphoma, osteosarcoma, melanoma, malignant glioma, B cell proliferative diseases, such as diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytes Leukemia, B-cell pro-ly
- the cancer is non-small cell lung cancer.
- the cancer is leukemia and lymphoma.
- the compounds of the invention are useful in the treatment of anaplastic lymphoma kinase (ALK) mediated diseases or disease states including immunological diseases or inflammations including, but not limited to, rheumatoid arthritis, osteoarthritis Rheumatoid spondylitis, gout, asthma, bronchitis, rhinitis, chronic obstructive pulmonary disease, cystic fibrosis, etc.
- ALK anaplastic lymphoma kinase
- the present invention provides a method for inhibiting ALK kinase and a method for treating the same, which comprises the steps of: using a compound according to the first aspect of the invention, or a pharmaceutically acceptable salt, hydrate or A solvate or a pharmaceutical composition according to the third aspect of the invention.
- the present invention has the following advantages:
- the present invention discloses a diphenylaminopyrimidine and a triazine compound of the formula I, a pharmaceutically acceptable salt, stereoisomer, hydrate or solvate thereof.
- the diphenylaminopyrimidine and triazine compounds of the present invention are useful for the treatment and/or prevention of diseases or conditions in which inhibition of ALK tyrosine kinase activity, such as cell proliferative diseases, cancer, immune diseases and the like.
- this series of compounds has better in vitro and in vivo activities and pharmacological effects, and also has obvious advantages in the dosage of drugs. Therefore, the diphenylaminopyrimidine and triazine compounds of the present application have good development prospects. And market potential.
- CD 3 CF 3 302.1 CD 3 CN 259.1 7 CD 2 CD 3 H 250.1 8 CD 2 CD 3 CH 3 264.1 9 CD 2 CD 3 Cl 284.1
- the compound (X) (1.47 g, 12 mmol) was added to a mixed solvent of dioxane and water (100 mL / 50 mL), followed by tris-(dibenzylideneacetone) dipalladium (1 g, 1.09). Ment), 2-biscyclohexylphosphine-2',6'-dimethoxybiphenyl (1.12 g, 2.72 mmol), compound (IX-2) (2.5 g, 10.9 mmol) and potassium phosphate (4.62 g, 21.8) Methyl) was added to the above mixture, nitrogen was bubbled for 15 minutes, and heated to reflux for 6 h, and the reaction was monitored by TLC.
- the compound (X) (1.47 g, 12 mmol) was added to a mixed solvent of dioxane and water (100 mL / 50 mL), tris-(dibenzylideneacetone) dipalladium [Pd 2 dba 3 ] ( 1 g, 1.09 mmol), 2-biscyclohexylphosphine-2',6'-dimethoxybiphenyl (1.12 g, 2.72 mmol), compound (IX-8) (2.5 g, 10.9 mmol) and potassium phosphate (4.62) g, 21.8 mmol) was added to the above mixture successively, and nitrogen was bubbled for 15 minutes, and the mixture was heated and refluxed for 6 hr.
- the reduction reaction of the nitrogen-containing heterocyclic compound (VIII) is carried out in the following manner, and the reaction route is as follows:
- the compound III and the compound IV are subjected to a coupling reaction under the catalysis of a palladium catalyst to obtain a compound II, and the reaction route is as follows:
- the compound II having a Boc protecting group is subjected to a deprotection reaction, and then subjected to a salt-forming reaction with a hydrogen chloride-ethanol solution to obtain a hydrochloride of the object compound (I) as shown in the formula. If the compound II has no protecting group, the deprotection reaction is not required, and the salt formation reaction can be directly carried out with the hydrogen chloride-ethanol solution.
- the reaction route map is as follows:
- the compound (II-3) (2.1 g, 3.3 mmol) was added to a solution of dichloromethane (10 mL) and trifluoroacetic acid (10 mL), and the mixture was stirred at room temperature for 2 hr. Washed with saturated sodium carbonate solution in dichloromethane (100 mL), dried, filtered and evaporated The free amine product was dissolved in dichloromethane (20 mL), added to a hydrogen chloride / ethanol solution (4M, 10 mL), stirred at room temperature for 2 h, washed with a white solid, filtered, and dried to give compound (I-3) (1.8 g, 95.2%).
- ALK anaplastic lymphoma kinase
- the in vitro kinase assay was performed using Cisbio's HTRF kinEASE TK kit, and the procedure was followed by reference to the kit instructions, which assay the inhibitory effect of the test compound on ALK enzyme activity in vitro.
- kit instructions which assay the inhibitory effect of the test compound on ALK enzyme activity in vitro.
- ALK wild type Cat. PV3867, Invitrogen
- ALK L1196M Cat. PV6168, Life technologies
- ALK F1174L Cat. PV6160, Life technologies
- a kinase reaction was initiated by adding 2 ⁇ l of ATP solution of the corresponding concentration of ALK enzyme to all wells, and the enzymatic reaction time of ALK was 60 minutes.
- the ALK test solution was prepared 5 minutes before the end of the kinase reaction. Streptavidin-XL665 and TK antibody europium cryptate (1:100) assay solutions were prepared using the detection buffer in the kit.
- the plate was mixed and allowed to react at room temperature for 1 hour, and then the fluorescence signal (320 nm stimulation, 665 nm, 615 nm emission) was detected by an ENVISION (Perkinelmer) instrument.
- the inhibition rate of each well was calculated from the fully active wells and the background signal wells, and the duplicate wells were averaged, and the half-inhibitory activity (IC50) of each test compound was fitted using a professional drawing analysis software PRISM 5.0.
- the inhibitory activity of each compound against ALK enzyme was as shown in Table 10 by the above method.
- NCI-H2228 human non-small cell lung cancer cell line RPMI 1640 + 10% FBS + 1% Sodium Pyruvate;
- NCI-H3122 human lung cancer cell line RPMI 1640 + 10% FBS + 1% Sodium Pyruvate;
- test compound was diluted with the medium to the corresponding concentration of action set, and the cells were added at 25 ⁇ l/well.
- the final concentration of the compound was diluted from 10 ⁇ M to 0 ⁇ M in 4 fold gradients for a total of 10 concentration points.
- tumor cell growth inhibition rate % [(A c - A s ) / (A c - A b )] ⁇ 100%
- a c negative control OA (cell + CCK-8 + DMSO)
- a b positive control OA (medium + CCK-8 + DMSO)
- the IC 50 curve was fitted and the IC 50 value was calculated using the software Graphpad Prism 5 and using the calculation formula log(inhibitor) vs.response.
- the growth inhibitory activities (IC 50 ) of different compounds against different tumor cells are shown in Table 11.
- SCID Beige mice female, 5-6 weeks old, weighing 18g ⁇ 2g, purchased from Beijing Huakang Biotechnology Co., Ltd., SPF-level environment breeding.
- NCI-H2228 cells were cultured in PRMI-1640 containing 10% fetal bovine serum FBS and 1% sodium pyruvate. The cells were cultured in a 5% CO 2 incubator at 37 °C.
- Tumor cells were inoculated established subcutaneous xenograft model: Tumor cells in logarithmic growth phase were collected and resuspended in PRMI-1640 base medium after the count, 1: 1 of Matrigel was added, the cell suspension adjusted to a concentration of 6 ⁇ 10 7 / ml . Tumor cells were inoculated subcutaneously in the right side of nude mice with a 1 mL syringe (4 gauge needle) at 6 x 10 6 /0.1 mL/mouse.
- the animals were randomly grouped according to the random block method, so that the difference of tumors in each group was less than 10% of the mean, and there were 5 groups in each group of 8 groups.
- the group was recorded as Day 0, and immediately after grouping.
- the compound of the present invention, I-3 and Ceritinib was orally administered once a day for 14 days and then for 7 days.
- the body weight and tumor size were measured twice a week during the experiment.
- the clinical symptoms were recorded daily.
- the animals were sacrificed by euthanization with CO 2 , the tumor was taken, the tumor weight was weighed and photographed, and the tumor average was calculated. value.
- mice When tumor-bearing mice grew to a measurable size, mice were randomized into 8 groups according to the mean tumor volume balance principle using SPSS 17.0 software.
- the compound AMX6001 was administered by intragastric administration at 30, 10, 3 mg/kg per day; the positive control drug AMX6003 was administered at a dose of 10 mg/kg per day, and the administration volume was 0.1 ml/10 g.
- the drug was administered once a day for 14 days, and the negative control group was given an equal amount of solvent (1% DMSO in physiological saline solution).
- the body weight and tumor diameter of the mice were measured 2 to 3 times per week. Tumor volume and relative tumor volume were calculated based on the measured data.
- RTV relative tumor volume
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Abstract
本发明涉及一种如式I所示的二苯氨基嘧啶及三嗪化合物,或其药学上可接受的盐、立体异构体、水合物或溶剂合物(I)其中:A为C或N;X、Y独立地选自氢、卤素、氰基、三氟甲基、烷氧基、烷基、芳环基、烯基、炔基、硝基;或者,X和Y与它们所连接的原子一起形成苯环或芳香杂环;R1为(AA),R2为CD3或CD2CD3;R3选自(BB),R4选自氢、甲基、三氟甲基、氰基或卤素;R5选自氢、烷基、取代和未取代的苯基、烯丙基或炔丙基;R6、R7独立地选自氢、烷基、取代和未取代的苯基、烯丙基、炔丙基;或者,R6和R7与它们所连接的氮原子一起形成取代或未取代的杂环烷基。本发明的二苯氨基嘧啶及三嗪化合物具有更好的药效学和药代动力学性能以及ALK激酶抑制活性功能。
Description
本发明涉及生物医药领域,尤其涉及一种二苯氨基嘧啶及三嗪化合物、其药用组合物及用途。
间变性淋巴瘤激酶(Anaplastic lymphoma kinase,ALK)是胰岛素受体酪氨酸激酶超家族的成员之一,目前已经发现了二十多种由不同的染色体重排后产生的ALK融合蛋白,它们参与包括间变大细胞淋巴瘤、弥漫性大B细胞淋巴瘤、炎性肌纤维母细胞瘤、神经母细胞瘤等的发病。ALK融合蛋白在约5-10%的非小细胞肺癌的发生中发挥根本性的作用。ALK融合蛋白的突变和过度表达与多种疾病相关,它参与复杂的信号转导,进而影响细胞增殖、分化和凋亡,ALK激酶抑制剂可以用于治疗癌症和自身免疫性疾病。
2011年8月,辉瑞公司的选择性ALK和c-Met双重抑制剂Crizotinib(商品名Xalkori)被美国FDA批准用于治疗非小细胞肺癌,国际专利申请WO2006021881A2公开了Crizotinib及其相关化合物。Crizotinib在临床应用中具有耐药性问题,由此激发了开发第二代ALK激酶抑制剂类药物,用于治疗非小细胞肺癌和其它疾病。
第二代ALK激酶抑制剂类药物是选择性的ALK激酶抑制剂,具有治疗癌症和细胞增殖性疾病以及其他相关疾病的用途,目前已有Ceritinib和Alectinib获批上市,用于治疗对Crizotinib产生耐药的ALK特异的非小细胞肺癌患者。另外,将ALK选择性抑制剂用于治疗白血病和淋巴瘤的研究也在进行中。WO2004080980A1和WO2008073687A2公开了Ceritinib相关的二苯氨基嘧啶化合物,WO2010143664A1公开了Alectinib相关化合物。
虽然以上几个上市的ALK激酶抑制剂一定程度上缓解了ALK特异性肺癌治疗及其耐药性问题,但是仍然存在活性和药效不足问题,这使得这几个药物的使用剂量都比较大,例如Crizotinib每日用量需要500毫克,而Alectinib和Ceritinib的每日用量都在750-1200毫克以上,这说明在治疗的有效性上,这些药都还远未达到理想目标。
WO2014173291A1公开了一系列氘代的二氨基嘧啶化合物,以改善Ceritinib的药效和成药性,但是相关的药效和成药性并无明显提高。对于已经发现的ALK激酶抑制剂来说,除了存在药效有待进一步提高,还存在成药性较差、耐药性突出和毒副作用明显等诸多问题,因此发现具有特异性抑制效果、低用量、更好成药性和抗耐药性、以及低毒性的新型化合物是非常有挑战性的,也是非常必要的。
发明内容
为解决上述技术问题,本发明提供了一种二苯氨基嘧啶及三嗪化合物,或其药学上可接受的盐、立体异构体、水合物或溶剂合物,其用途及药用组合物。所述二苯氨基嘧啶及三嗪化合物,或其药学上可接受的盐、立体异构体、水合物或溶剂合物具有更好的药效学和药代动力学性能,能够有效抑制ALK激酶活性。
为了实现以上目的,本发明采用了以下的技术方案:
在一方面,本发明提供了一种如式I所示的二苯氨基嘧啶及三嗪化合物,或其药学上可接受的盐、立体异构体、水合物或溶剂合物:
其中:
A为C或N;
X、Y独立地选自氢、卤素、氰基、三氟甲基、烷氧基、烷基、芳环基、烯基、炔基或硝基;或者,X和Y与它们所连接的(C,或C和N)原子一起形成苯环或芳香杂环,所述芳香杂环含有氧、硫和氮杂原子中的一种或几种;
R2为CD3或CD2CD3;
R4选自氢、甲基、三氟甲基、氰基或卤素;
R5选自氢、烷基、取代和未取代的苯基、烯丙基或炔丙基;
R6、R7独立地选自氢、烷基、取代和未取代的苯基、烯丙基、炔丙基;或者,R6和R7与它们所连的氮(N)原子一起形成取代或未取代的杂环烷基,杂环烷基含有氧、硫、氮、亚砜基和砜基中的一种或几种。
本发明中,芳香杂环优选吖啶、咔唑、噌啉、喹喔啉、吡唑、吲哚、苯并三唑、呋喃、噻吩、苯并噻吩、苯并呋喃、喹啉、异喹啉、噁唑、异噁唑、吲哚、吡嗪、哒嗪、吡啶、嘧啶、吡咯或四氢喹啉。
杂环烷基优选噁唑啉、氧环丁基、吡喃基、四氢吡喃基、氮杂环丁烷基、1,4-二噁烷基、六氢氮杂草基、哌嗪基、哌啶基、吡咯烷基、吗啉基、硫代吗啉基、二氢呋喃基、二氢咪唑基、二氢吲哚基、二氢异噁唑基、二氢异噻唑基、二氢噁二唑基、二氢噁唑基、二氢吡嗪基、二氢吡唑基、二氢吡啶基、二氢嘧啶基、二氢吡咯基、二氢四唑基、二氢噻二唑基、二氢噻唑基、二氢噻吩基、二氢三唑基、二氢氮杂环丁烷基、四氢呋喃基或四氢噻吩基。
本发明中,烷基优选C1-C10烷基,烯基优选C2-C12烯基,更优选C2-C4乙烯基,进一步优选乙烯基。炔基优选C2-C12炔基,更优选C2-C4炔基,进一步优选乙炔基。
优选地,二苯氨基嘧啶及三嗪化合物,具体为以下任一化合物:
(N4-(2-(异丙基磺酰基)苯基)-N2-(2-D3-甲氧基-5-甲基-4-(哌啶-4-基)苯基)嘧啶-2,4-二氨);
(5-氟-N4-(2-(异丙基磺酰基)苯基)-N2-(2-D3-甲氧基-5-甲基-4-(哌啶-4-基)苯基)嘧啶-2,4-二氨);
(5-氯-N4-(2-(异丙基磺酰基)苯基)-N2-(2-D3-甲氧基-5-甲基-4-(哌啶-4-基)苯基)嘧啶-2,4-二氨);
(5-溴-N4-(2-(异丙基磺酰基)苯基)-N2-(2-D3-甲氧基-5-甲基-4-(哌啶-4-基)苯基)
嘧啶-2,4-二氨);
(N4-(2-(异丙基磺酰基)苯基)-N2-(2-甲氧基-5-甲基-4-(哌啶-4-基)苯基)-5-(三氟甲基)嘧啶-2,4-二氨);
(2-(异丙基磺酰基)苯基)氨基)-2-((2-D3-甲氧基-5-甲基-4-(哌啶-4-基)苯基)氨基)嘧啶-5-腈);
(N4-(2-(异丙基磺酰基)苯基)-5-甲氧基-N2-(2-D3-甲氧基-5-甲基-4-(哌啶-4-基)苯基)嘧啶-2,4-二氨);
(N4-(2-(异丙基磺酰基)苯基)-N2-(2-D3-甲氧基-5-甲基-4-(哌啶-4-基)苯基)-5-甲基嘧啶-2,4-二氨);
(5-乙基-N4-(2-(异丙基磺酰基)苯基)-N2-(2-D3-甲氧基-5-甲基-4-(哌啶-4-基)苯基)嘧啶-2,4-二氨);
(N4-(2-(异丙基磺酰基)苯基)-N2-(2-D3-甲氧基-5-甲基-4-(哌啶-4-基)苯基)-5-硝基嘧啶-2,4-二氨);
(N4-(2-(异丙基磺酰基)苯基)-N2-(2-D3-甲氧基-5-甲基-4-(哌啶-4-基)苯基)-5-苯基嘧啶-2,4-二氨);
(N4-(2-(异丙基磺酰基)苯基)-N2-(2-D3-甲氧基-5-甲基-4-(哌啶-4-基)苯基)-5-乙烯基嘧啶-2,4-二氨);
(5-乙炔基-N4-(2-(异丙基磺酰基)苯基)-N2-(2-D3-甲氧基-5-甲基-4-(哌啶-4-基)苯基)嘧啶-2,4-二氨);
(5-氯-N2-(2-D6-乙氧基-5-甲基-4-(哌啶-4-基)苯基)-N4-(2-(异丙基磺酰基)苯基))嘧啶-2,4-二氨);
(N4-(2-(异丙基磺酰基)苯基)-N2-(2-D3-甲氧基-4-(4-吗啡啉哌啶-1-基)苯基)喹唑啉-2,4-二氨);
(N4-(2-(异丙基磺酰基)苯基)-N2-(2-D3-甲氧基-4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-7H-吡咯并[2,3-d]嘧啶-2,4-二氨);
(N4-(2-(异丙基磺酰基)苯基)-N2-(2-D3-甲氧基-4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4-二氨);
N2-(4-(4-(二甲氨基)哌啶-1-基)-2-D3-甲氧基苯基)-N4-(2-(异丙基磺酰基)苯基)噻吩并[2,3-d]嘧啶-2,4-二氨;
(N2-(4-(4-(二甲氨基)哌啶-1-基)-2-D3-甲氧基苯基)-N4-(2-(异丙基磺酰基)
苯基)噻吩并[3,2-d]嘧啶-2,4-二氨);
(5-氯-N4-(2-(异丙基磺酰基)苯基)-N2-(2-D3-甲氧基-4-(哌嗪-1-基)苯基)嘧啶-2,4-二氨);
(5-氯-N2-(2-D3-甲氧基-4-(哌啶-4-基)苯基)-N4-(2-(异丙基磺酰基)苯基)嘧啶-2,4-二氨)
(5-氯-N2-(5-氟-2-D3-甲氧基-4-(哌啶-4-基)苯基)-N4-(2-(异丙基磺酰基)苯基)嘧啶-2,4-二氨);
(5-氯-N2-(5-氯-2-D5-乙氧基-4-(哌啶-4-基)苯基)-N4-(2-(异丙基磺酰基)苯基)嘧啶-2,4-二氨);
(5-氯-N2-(5-氯-2-D3-甲氧基-4-(哌啶-4-基)苯基)-N4-(2-(异丙基磺酰基)苯基)嘧啶-2,4-二氨);
(5-氯-N4-(2-(异丙基磺酰基)苯基)-N2-(2-D3-甲氧基-4-(哌啶-4-基)-5-(三氟甲基)苯基)嘧啶-2,4-二氨);
(5-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-4-D3-甲氧基-2-(哌啶-4-基)苯腈);
(N2-(2-D3-甲氧基-4-(哌嗪-1-基)-5-甲基-苯基)-N4-(2-(异丙基磺酰基)苯基)-1,3,5-三嗪-2,4-二氨);
(N2-(2-(异丙基磺酰基)苯基)-N4-(2-D3-甲氧基-5-甲基-4-(哌啶-4-基)苯基)-1,3,5-三嗪-2,4-二氨);
(N2-(2-D3-甲氧基-4-(哌嗪-1-基)苯基)-N4-(2-(异丙基磺酰基)苯基)-1,3,5-三嗪-2,4-二氨);
(5-氯-N2-(2-D5-乙氧基-4-(哌啶-4-基)苯基)-N4-(2-(异丙基磺酰基)苯基)嘧啶-2,4-二氨);
(N4-(2-(异丙基磺酰基)苯基)-N2-(2-D3-甲氧基-5-甲基-4-(哌啶-4-基)苯基)喹唑啉-2,4-二氨);
(N4-(2-(异丙基磺酰基)苯基)-N2-(2-D3-甲氧基-5-甲基-4-(哌啶-4-基)苯基)-7H-吡咯并[2,3-d]嘧啶-2,4-二氨);
(N4-(2-(异丙基磺酰基)苯基)-N2-(2-D3-甲氧基-5-甲基-4-(哌啶-4-基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4-二氨);
(N4-(2-(异丙基磺酰基)苯基)-N2-(2-D3-甲氧基-5-甲基-4-(哌啶-4-基)苯基)噻
吩并[2,3-d]嘧啶-2,4-二氨);
(5-氯-N4-(2-(异丙基磺酰基)苯基)-N2-(2-D3-甲氧基-4-(4-硫代吗啉哌啶-1-基)苯基)嘧啶-2,4-二氨);
(N2-(4-(4-氨-[1,4'-联哌啶]-1'-基)-2-D3-甲氧基苯基)-5-氯-N4-(2-(异丙基磺酰基)苯基)嘧啶-2,4-二氨);
(5-氯-N4-(2-(异丙基磺酰基)苯基)-N2-(2-D3-甲氧基-4-(4-吗啡啉哌啶-1-基)苯基)嘧啶-2,4-二氨);
(N2-(2-(异丙基磺酰基)苯基)-N4-(2-D3-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-1,3,5-三嗪-2,4-二氨);
(5-氯-N4-(2-(异丙基磺酰基)苯基)-N2-(2-D3-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)嘧啶-2,4-二氨);
(2-((5-氯-2-((4-(4-(二甲氨基)哌啶-1-基)-2-D3-甲氧基苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧化磷);
(5-氯-N4-(2-(二甲基磷酰基)苯基)-N2-(2-D3-甲氧基-5-甲基-4-(哌啶-4-基)苯基)嘧啶-2,4-二胺);
(N2-(2-(异丙基磺酰基)苯基)-N4-(2-D3-甲氧基-4-(4-哌啶-4-基)苯基)-1,3,5-三嗪-2,4-二氨);
(5-氯-N4-(2-(异丙基磺酰基)苯基)-N2-(2-D3-甲氧基-4-(哌嗪-1-基)-5-甲基-苯基)嘧啶-2,4-二胺)。
上述化合物的具体结构分别如下:
在另一方面,本发明还提供了上述式I所示的二苯氨基嘧啶及三嗪化合物的制备方法,包括以下步骤:将化合物II进行脱保护反应,得到如式I所示的二苯基嘧啶及三嗪化合物;
其中,A、X、Y、R1、R2、R3和R4的定义均同上所述。脱保护和成盐反应可以采用本领域中该类反应的常规方法和条件。
本发明中,所述的如式I所示的二苯基嘧啶及三嗪化合物的制备方法,进一步包括以下
步骤:在钯催化剂的催化下,将化合物III与化合物IV进行偶联反应,得到化合物II。
其中,A、X、Y、R1、R2、R3和R4的定义均同上所述。PG为保护基团,可以是Boc(叔丁氧羰基)、CBz(苄氧羰基)或Troc(三氯乙氧羰基),优选Boc(叔丁氧羰基)。
本发明中,上述如式I所示的二苯基嘧啶及三嗪化合物的制备方法进一步包括以下步骤:将化合物V与化合物VI进行偶联反应,得到化合物III;
其中,A、X、Y、R1、R2、R3和R4的定义均同上所述;所述的偶联可以采用本领域中该类反应的常规方法和条件。
本发明中,当R3为哌啶基时,如式I所示的二苯基嘧啶及三嗪化合物的制备方法进一步包括以下步骤:将化合物VII的R3基团中的氨基进行保护反应,得到所述的化合物IV;
其中,R1、R2、R3和R4的定义均同上所述;PG为保护基团,可以是Boc(叔丁氧羰基)、CBz(苄氧羰基)或Troc(三氯乙氧羰基),优选Boc(叔丁氧羰基);所述的保护反应可以采用本领域中该类反应的常规方法和条件。
本发明中,当R3为哌啶基时,如式I所示的二苯基嘧啶及三嗪化合物的制备方法进一步包括以下步骤:将化合物VIII的硝基和R3’中的吡啶基进行还原反应,得到化合物VII;
其中,R1、R2、R3、R3’和R4的定义均同上所述;还原反应可以采用本领域中该类反应的常规方法和条件。
本发明中,当R3为哌啶基、R3’为吡啶基时,如式I所示的二苯基嘧啶及三嗪化合物的制备方法进一步包括以下步骤:将化合物IX和化合物X进行Suzuki偶联反应,得到化合物VIII;
其中,R1、R2、R3’和R4的定义均同上所述;Suzuki偶联反应可以采用本领域中该类反应的常规方法和条件。
本发明中,如式I所示的二苯基嘧啶及三嗪化合物的制备方法进一步包括以下步骤:将化合物XI进行取代反应,得到化合物IX;
其中,R1、R2和R4的定义均同上所述;所述的还原反应可以采用本领域中该类反应的常规方法和条件。
另外,本发明中,当R3为单PG保护的哌嗪基时,如式I所示的二苯基嘧啶及三嗪化合物的制备方法,其进一步包括以下步骤:将化合物VIII的硝基进行还原,得到所述的化合物IV即可。
使用本发明描述的合成方法,以及本领域已知的合成方法,并通过本领域已知的常规方法纯化,例如过滤、重结晶、色谱、柱层析、蒸馏及其组合,就可以获得较高纯度和收率的如式I所示的二苯氨基嘧啶及三嗪衍生物。
本发明中,术语“烷基”为包括具有指定碳原子数目的支链或直链的饱和脂肪族烃基;如在“C1-C10烷基”中定义为包括在直链或者支链结构中具有1、2、3、4、5、6、7、8、9或者10个碳原子的基团。例如,“C1-C10烷基”具体包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、戊基、己基、庚基、辛基、壬基和癸基等。
本发明中,术语“烷氧基”表示烷基与氧原子连接后的生成基团,即“RO-”,R为烷基。
本发明中,术语“环烷基”指全碳单环或多环基团,优选3~20个碳所形成的1~3个环的环烷基,更优选3~10个碳,例如:环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环癸烷或环十二烷基。
本发明中,术语“杂环烷基”在此单独或作为另一个基团的一部分使用时,指包含1~4个杂原子(如氮、氧和硫中的一种或多种)的4~12元单环或多环基团,其中每个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子体系。此外,任何杂环烷基环可以稠合于环烷基、芳基、杂芳基或杂环烷基环上。在此定义范围内的杂环烷基包括但不限于:噁唑啉、氧环丁基、吡喃基、四氢吡喃基、氮杂环丁烷基、1,4-二噁烷基、六氢氮杂草基、哌嗪基、哌啶基、吡咯烷基、吗啉基、硫代吗啉基、二氢呋喃基、二氢咪唑基、二氢吲哚基、二氢异噁唑基、二氢异噻唑基、二氢噁二唑基、二氢噁唑基、二氢吡嗪基、二氢吡唑基、二氢吡啶基、二氢嘧啶基、二氢吡咯基、二氢四唑基、二氢噻二唑基、二氢噻唑基、二氢噻吩基、二氢三唑基、二氢氮杂环丁烷基、四氢呋喃基和四氢噻吩基及其N-氧化物。杂环烷基可以经其中的碳原子或者杂原子与其他基团进行连接。
本发明中,术语“烯基”是指含有指定数目碳原子和至少一个碳碳双键的直链、支链或者环状非芳香烃基。优选存在一个碳碳双键,并且可以存在高达四个非芳香碳碳双键。由此,“C2~C12烯基”是指具有2~12个碳原子的烯基。“C2~C4”烯基是指具有2~4个碳原子的烯基,包括乙烯基、丙烯基、2-甲基-丙烯基、1-丁烯基和2-丁烯基。烯基的直链、支链或者环部分可以含有双键。
本发明中,所述的术语“炔基”是指含有指定数目碳原子和至少一个碳碳三键的直链、支链或者环状烃基。其中可以存在高达三个碳碳三键。由此,“C2~C12炔基”是指具有2~12个碳原子的炔基。“C2~C4炔基”是指具有2~4个碳原子的炔基,包括乙炔基、丙炔基、1-丁炔基和2-丁炔基等。
本发明中,术语“芳环”是指任何稳定的可高达7个原子的单环或者双环碳环,其中至少一个环是芳香环。芳环基的实例包括苯基、萘基、四氢萘基、2,3-二氢化茚基、联苯基、菲基、蒽基或者苊基(acenaphthyl)。可以理解,在芳基取代基是二环取代基且其中一个环是非芳香环的情况中,连接是通过芳环进行的。
本发明中,术语“芳香杂环”表示可高达7个原子的稳定单环或者二环,其中至少一个环是芳香环并且含有1-4个选自O、N和S的杂原子;芳香杂环的实例包括但不限于:吖啶、咔唑、噌啉、喹喔啉、吡唑、吲哚、苯并三唑、呋喃、噻吩、苯并噻吩、苯并呋喃、喹啉、
异喹啉、噁唑、异噁唑、吲哚、吡嗪、哒嗪、吡啶、嘧啶、吡咯和四氢喹啉。正如以下杂环的定义一样,“芳香杂环”还应当理解为包括任何含氮杂芳基的N-氧化物衍生物。在其中杂环芳基取代基是二环取代基并且一个环是非芳香环或者不包含杂原子的情况下,可以理解,连接分别通过芳环或者通过包含环的杂原子进行。
本发明中,确定了碳数范围的“Cx1-Cy1”烷基(x1和y1为整数)、环烷基、杂环烷基、芳基和杂芳基,如“C1-12烷基”,均表示未包含取代基的C1-12烷基。
本发明中,术语“卤素”表示氟、氯、溴或碘。
对于各个变量,上述基团的任意组合也在本文考虑之中。可以理解的是:本文所提供的化合物上的取代基和取代方式可以由本领域普通技术人员进行选择,以便提供化学上稳定的、且可以使用本领域已知的技术以及本文阐述的技术合成的化合物。
使用本领域技术人员已知的标准合成技术或使用本领域已知的合成方法与本文描述的合成方法组合,可以合成如式I所示的二苯氨基嘧啶及三嗪衍生物中任一个的化合物。另外,本文给出的溶剂、温度和其它反应条件可以根据本领域技术而改变。作为进一步的指导,也可以利用以下的合成方法。
在某些实施方式中,本文提供的是如式I所示的二苯氨基嘧啶及三嗪衍生物的制备方法及其使用方法。在某些实施方式中,本文描述的化合物可以使用以下合成的方案合成,也可以使用与下述类似的方法,通过选择适当的起始原料来合成目标化合物。
用于合成本文描述的化合物的起始原料可以被合成或可以从商业来源获得。本文描述的化合物,和其它相关具有不同取代基的化合物可以使用本领域技术人员已知的技术和原料合成,例如在Paquette的《Encyclopedia of Reagents for Organic Synthesis》(Wiley 2009),March的《Advanced Organic Chemistry》第四版,(Wiley1992);Carey和Sundberg的《Advanced Organic Chemistry》第四版,A卷和B卷(Plenum 2000,2001);Green和Wuts的《Protective Groups in Organic Synthesis》第三版,(Wiley1999);Fieser和Fieser的《Reagents for Organic Synthesis》第1-17卷(John Wiley and Sons,1991);《Organic Reactions》第1-40卷(John Wiley and Sons,1991),以及Larock的《Comprehensive Organic Transformations》(VCH PublishersInc.,1999)(通过引用将其全部结合到本文中)。制备本文公开的化合物的一般方法可以来自本领域已知的反应,并且该反应可以通过由本领域技术人员所认为适当的试剂和条件修改,以合成目标化合物分子。以下的合成方法可以作为基础指导利用。
每个反应结束后,反应产物可以使用常规技术进行后处理(分离和纯化),包括但不限
于过滤、蒸馏、结晶、色谱等方法。这些产物可以使用常规分析方法进行表征,包括物理常数和图谱数据(m.p、HPLC、LC-MS、NMR和旋光度等)。本文描述的化合物可以使用本文描述的合成方法制备为单一异构体。
药物组合及制剂:
在另一方面,本发明提供一种药用组合物,其包含本发明任一化合物或其药学上可接受的盐、立体异构体、水合物或溶剂合物,以及一种或多种药学上可接受的载体或赋形剂。可以使用一种或多种生理可接受的载体以常规的方式配制药用组合物,所述载体包括赋形剂和辅料,其有利于将活性化合物加工为可以药用的制剂。适当的制剂取决于选择的给药途径。任何熟知的技术、载体和赋形剂可以被适当使用,并且如本领域所理解的。
本发明的药用组合物是指本文描述的化合物实例的中任一个化合物与其它化学组分的混合物,例如载体、稳定剂、抗氧化剂、崩解剂、稀释剂、分散剂、填充剂、矫味剂、悬浮剂、助流剂、增溶剂、表面活性剂、湿润剂、增稠剂和/或赋形剂。所述药用组合物有利于化合物给予生物体。在实践本发明提供的治疗或使用方法中,以药用组合物将治疗有效量的本发明描述的化合物给予患有待治疗的疾病、障碍或病症的哺乳动物。优选地,所述哺乳动物是人。治疗有效量可以变化很大,取决于疾病的严重程度、受治疗者的年龄和相对健康状况、使用的化合物的功效等其它因素。所述化合物可以单独使用或者与作为混合物的组分的一种或多种治疗药联合使用。
药用组合物将包括至少一种本发明描述的化合物中任一个的化合物,以游离酸或游离碱的形式作为活性成分,或以药物可接受的盐形式作为活性成分。另外,本发明描述的方法和药用组合物包括使用N-氧化物、晶体形式(也称为多晶型)、以及这些具有相同类型的活性的化合物的活性代谢物。在一些情况下,化合物可以互变异构体存在。所有的互变异构体包括在本发明提供的化合物的范围内。另外,本发明描述的化合物能以非溶剂化物以及溶剂化物的形式与药物可接受的溶剂如水、乙醇等一起存在。本发明提供的化合物的溶剂化物形式也被认为在此公开。
在又一方面,本发明提供了一种药物制剂,包括上述二苯氨基嘧啶及三嗪化合物,或其药学上可接受的盐、立体异构体、水合物或溶剂合物作为有效药物成分。本发明描述的药物制剂可以通过多种给药途径给予受治疗者,所述给药途径包括但不限于口服、肠胃外(例如静脉内、皮下、肌内)、鼻内、口腔含化、局部、直肠或经皮给药途径。本文描述的药物制剂包括但不限于水成液分散体、自乳化分散体、固溶体、脂质体分散剂、气雾剂、固体剂型、散剂、即释制剂、控释制剂、速溶制剂、片剂、胶囊剂、丸剂、缓释制剂、延释制剂、脉动
释放制剂、多颗粒制剂和混合的即时和控释制剂。
用于口服的药物制剂可以通过将一种或多种固体赋形剂与一种或多种本文描述的化合物混合而获得,任选地磨碎得到的混合物,如果需要,在加入合适的辅料后进行混合物制粒,以获得片剂或锭剂芯。合适的赋形剂(例如)包括:填充剂,例如糖类,包括乳糖、蔗糖、甘露醇或山梨醇等;纤维素制剂,例如玉米淀粉、小麦淀粉、米淀粉、马铃薯淀粉、明胶、西黄蓍胶、甲基纤维素、微晶纤维素、羟丙基甲基纤维素、羧甲基纤维素钠等等;表面活性剂,例如聚乙烯吡咯烷酮(PVP或聚维酮)或磷酸钙等。如果需要,可以加入崩解剂,例如交联交联羧甲纤维素钠、聚乙烯吡咯烷酮、琼脂或海藻酸或其盐如海藻酸钠。
可以口服使用的药物制剂包括由明胶制造的推入式胶囊、以及由明胶和增塑剂例如甘油或山梨醇制造的软的密封胶囊。所述推入式胶囊能包含活性成分,其混合于填料如乳糖、粘合剂如淀粉和/或润滑剂如滑石粉或硬脂酸镁,和任选的稳定剂。在软胶囊中,活性化合物可以溶解或悬浮在合适的液体中,例如脂肪油、液状石蜡或液体聚乙二醇。另外,可以加入稳定剂。用于口服给药的所有制剂应该是适合这种给药的剂型。
在一些实施方式中,本发明公开的固体剂型可以是片剂形式(包括混悬片剂、速溶片剂、咀嚼崩解片剂、速崩片剂、泡腾片剂或胶囊形片剂),丸剂、散剂(包括无菌包装的散剂,非必需散剂或泡腾散剂),胶囊剂(包括软胶囊剂或硬胶囊剂,例如用动物来源的明胶制造的胶囊或者用植物来源的HPMC制造的胶囊或“分散型胶囊”)、固体分散体、固溶体、生物可蚀性剂型、控制释放制剂、脉动释放剂型、多颗粒剂型、小药丸、颗粒剂或气雾剂。在其它实施方式中,所述药物制剂是粉末形式的。在又一些实施方式,所述药物制剂是片剂形式的,包括但不限于速溶片剂。另外,本发明描述的药物制剂可以作为单一胶囊剂或以多胶囊剂型用药。在一些实施方式中,药物制剂以两个、或三个、或四个胶囊剂或片剂用药。
药用组合物将包括至少一种本发明描述的化合物中任一个的化合物的制剂,适合肌内、皮下或静脉内注射,可以包括生理可接受的无菌水或非水的溶液剂、分散体、混悬剂或乳剂、和无菌粉针剂,所述无菌粉针剂用于重新配制无菌注射溶液剂或分散体。合适的水性和非水性载体、稀释剂、溶剂或溶媒的实例包括水、乙醇、多元醇(丙二醇、聚乙二醇、甘油、克列莫(cremophor)等)、其合适的混合物、植物油(如橄榄油)和注射用有机酯如油酸乙酯。可以维持适当的流动性,例如通过使用包衣如卵磷脂;分散体时,通过维持所需的颗粒大小;和通过使用表面活性剂。适合用于皮下注射的制剂也可以包含添加剂如防腐剂、润湿剂、乳化剂和分散剂。可以通过各种抗细菌剂和抗真菌剂确保防止微生物生长,例如对羟基苯甲酸酯、三氯叔丁醇、苯酚、山梨酸,等等。也可以根据需要,包括等渗剂,例如糖、氯化钠等。
延长可注射药物形式的吸收可以通过使用延迟吸收剂带来,例如单硬脂酸铝和明胶。
本发明还涉及在制药领域中公知的用于包括眼内的、鼻内的和耳内的输送的各种药物组合物。药物配方包括所述活性化合物的水性眼用溶液,其可以诸如滴眼剂的水溶性形式存在,或以结冷胶或水凝胶;眼用软膏;眼用混悬液,例如微粒,悬浮在液体载体介质中的包含药物的小聚合粒子,脂溶性制剂,和微球;以及眼用嵌入剂。为了稳定性和舒适性,这些合适的药物制剂最经常和优选地制造成无菌的、等渗的和缓冲的制剂。药物组合物也包括滴剂和喷雾剂,其常在许多方面模拟鼻分泌物来确保正常纤毛作用的维持。正如本领域的技术人员公知的那样,合适的制剂最常和优选地是等渗的,保持pH值5.5到6.5的轻度缓冲的,且最经常和优选地包括抗菌性防腐剂和适当的药物稳定剂。用于耳内转运的药物制剂包括悬浮液和在耳内局部应用的软膏。用于这些耳用制剂的普通溶剂包括甘油和水。
本发明还涉及任一项所述的化合物中任一化合物或其药学上可接受的盐、立体异构体、水合物或溶剂合物可以经过口服、胃肠道外(静脉内、肌肉内、皮下等)、经肺部、局部、皮肤等给药方式施用于哺乳动物,例如人。本发明化合物的人剂量可以大约为0.1mg至大约1000mg范围。
在另一方面,本发明还提供任一化合物或其药学上可接受的盐、立体异构体、水合物、溶剂合物、活性代谢产物及前体药物在制备药物中的用途,可以单独给药,或者与其他治疗药物联合用药,所述的其他治疗药物为癌症、心血管疾病、感染、炎症、免疫性疾病、细胞增殖性疾病、器官移植、病毒性疾病或代谢性疾病的药物。
联合用药包括但不限于阿霉素、更生霉素、博来霉素、长春碱、顺铂、阿西维辛;阿柔比星;盐酸阿考达唑;阿克罗宁;阿多来新;阿地白介素;六甲蜜胺;安波霉素;醋酸阿美蒽醌;氨鲁米特;安吖啶;阿那曲唑;安曲霉素;门冬酰胺酶;曲林菌素;阿扎胞苷;阿扎替派;阿佐霉素;巴马司他;苯佐替派;比卡鲁胺;盐酸比生群;二甲磺酸双奈法德;比折来新;硫酸博来霉素;布喹那钠;溴匹立明;白消安;放线菌素C;卡鲁睾酮;卡醋胺;卡贝替姆;卡铂;卡莫司汀;盐酸卡柔比星;卡折来新;西地芬戈;苯丁酸氮芥;西罗霉素;克拉屈滨;甲磺酸克立那托;环磷酰胺;阿糖胞苷;达卡巴嗪;盐酸柔红霉素;地西他滨;右奥马铂;地扎呱宁;甲磺酸地扎呱宁;地吖醌;多柔比星;盐酸多柔比星;屈洛昔芬;柠檬酸屈洛昔芬;丙酸曲他雄酮;达佐霉素;依达曲沙;盐酸依氟鸟氨酸;依沙芦星;恩洛铂;恩普氨酯;依匹哌啶;厄布洛唑;盐酸依索比星;雌莫司汀;雌莫司汀磷酸钠;依他硝唑;依托泊苷;磷酸依托泊苷;氯苯乙嘧胺;盐酸法倔唑;法扎拉滨;芬维A胺;氟尿苷;磷酸氟达拉滨;5-氟尿嘧啶;氟西他滨;磷喹酮;福司曲星钠;吉西他滨;盐酸吉西他滨;卡培
他滨;硼替佐米;卡非佐米;阿法替尼;阿瓦斯丁(avastin);贝沙罗汀;骨化三醇;培美曲塞二钠;羟基脲;盐酸伊达比星;异环磷酰胺;伊莫福新;白细胞介素II(包括重组白细胞介素II或rIL2)、干扰素α-2a;干扰素α-2b;干扰素α-n1;干扰素α-n3;干扰素β-1a;干扰素γ-1b;异丙铂;盐酸伊立替康;醋酸兰瑞肽;来曲唑;醋酸亮丙瑞林;盐酸利阿唑;洛美曲索钠;洛莫司汀;盐酸洛索蒽醌;马索罗酚;美登素;盐酸氮芥;醋酸甲地孕酮;醋酸美仑孕酮;美法仑;美诺立尔;巯嘌呤;甲氨蝶呤;甲氨蝶呤钠;氯苯氨啶;美妥替哌;米丁度胺;米托卡星;丝裂红素;米托洁林;米托马星;丝裂霉素;米托司培;米托坦;盐酸米托蒽醌;麦考酚酸;诺考达唑;诺拉霉素;奥马铂;奥昔舒仑;培门冬酶;培利霉素;奈莫司汀;硫酸培洛霉素;培磷酰胺;哌泊溴烷;哌泊舒凡;盐酸吡罗蒽醌;普卡霉素;普洛美坦;卟吩姆钠;紫菜霉素;泼尼莫司汀;盐酸丙卡巴肼;嘌呤霉素;盐酸嘌呤霉素;吡唑呋啉;利波腺苷;洛太米特;沙芬戈;盐酸沙芬戈;司莫司汀;辛曲秦;磷乙酰天冬氨酸钠;司帕霉素;盐酸锗螺胺;螺莫司汀;链黑菌素;链佐星;磺氯苯脲;他利霉索;替可加兰钠;替加氟;盐酸替洛蒽醌;替莫泊芬;替尼泊苷;替罗昔隆;睾内酯;硫咪嘌呤、硫鸟嘌呤、塞替派;噻唑呋林;替拉扎明;枸橼酸托瑞米芬;醋酸曲托龙、醋酸7-甲诺酮;磷酸曲西立滨;三甲曲沙;葡萄糖醛酸三甲曲沙;曲普瑞林;盐酸妥布氯唑;尿嘧啶氮芥;乌瑞替派;代普肽;维替泊芬;硫酸长春碱;硫酸长春新碱;长春地辛;硫酸长春地辛;硫酸长春匹定;硫酸长春甘酯;硫酸长春西醇;长春瑞滨;硫酸长春罗定;硫酸长春利定;伏氯唑;折尼铂;净司他丁;盐酸佐柔比星、米托蒽酮、紫杉醇、丙卡巴肼、赛替哌、血管生成抑制剂、喜树碱、地塞米松、阿司匹林、乙酰氨基酚、吲哚美辛、布洛芬、酮洛芬、美洛昔康、皮质类固醇和肾上腺皮质类固醇。
治疗用途:
本发明还涉及任一化合物或其药学上可接受的盐、立体异构体、水合物或溶剂合物在制备药物中的用途,所述药物为ALK酪氨酸激酶抑制剂,或用于预防或治疗受益于ALK酪氨酸激酶活性抑制的疾病、病症或症状。所述药物用于治疗和/或预防哺乳动物(包括人)的与化合物用于抑制间变性淋巴瘤激酶(ALK)活性或用于治疗受益于间变性淋巴瘤激酶(ALK)活性抑制的疾病、病症或病状的用途。
在某些实施方案中,间变性淋巴瘤激酶(ALK)介导的疾病或疾病状态的实例包括但不限于癌症、细胞增值性疾病、炎症、感染、免疫性疾病、器官移植、病毒性疾病、心血管疾病或代谢性疾病。
本发明化合物可用于治疗间变性淋巴瘤激酶(ALK)介导疾病或疾病状态的实例包括的癌
症但不限于头部癌、甲状腺癌、颈癌、眼癌、皮肤癌、口腔癌、咽喉癌、食道癌、胸癌、骨癌、血癌、骨髓癌、肺癌、头颈癌、结肠癌、乙状结肠癌、直肠癌、结肠癌、鼻咽癌、胃癌、前列腺癌、乳腺癌、卵巢癌、子宫癌、肾癌、肝癌、胰腺癌、膀胱癌、脑癌、肠癌、心脏癌、肾上腺癌、皮下组织癌、淋巴结癌、淋巴瘤、骨肉瘤、黑色素瘤、恶性神经胶质瘤、B细胞增生性疾病,例如弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、慢性淋巴细胞淋巴瘤、慢性淋巴细胞白血病、B细胞前淋巴细胞性白血病、淋巴浆细胞淋巴瘤/瓦尔登斯特伦巨球蛋白血症、脾边缘区淋巴瘤、浆细胞性骨髓瘤、浆细胞瘤、结外边缘区B细胞淋巴瘤、淋巴结边缘区B细胞淋巴瘤、套细胞淋巴瘤、纵隔(胸腺)大B细胞淋巴瘤、血管内大B细胞淋巴瘤、原发性渗出性淋巴瘤、伯基特淋巴瘤/白血病或淋巴瘤样肉芽肿病。
在另一优选例中,所述的癌症为非小细胞肺癌。
在另一优选例中,所述的癌症为白血病和淋巴瘤。
在另一优选例中,本发明化合物可用于治疗间变性淋巴瘤激酶(ALK)介导疾病或疾病状态的实例包括的免疫性疾病或炎症包括但不限于:类风湿性关节炎、骨关节炎、类风湿性脊椎炎、痛风、哮喘、支气管炎、鼻炎、慢性阻塞性肺病、囊性纤维化病等。
本发明提供了一种ALK激酶的抑制方法以及与其相关的疾病治疗方法,它包括步骤:给需要治疗的对象使用本发明第一方面所述的化合物或其药学上可接受的盐、水合物或溶剂合物,或使用本发明第三方面所述的药物组合物。应当理解,在本发明范围内,上述的各项技术特征和在实施例中具体描述的各技术特征之间都可以相互结合,从而构成新的或优选的技术方案,由于篇幅所限,在此不再详述。
借由上述方案,本发明具有以下优点:
本发明公开了式I所示的二苯氨基嘧啶及三嗪化合物,其药学上可接受的盐、立体异构体、水合物或溶剂合物。本发明的二苯氨基嘧啶及三嗪化合物可用于治疗和/或预防ALK酪氨酸激酶活性抑制的疾病或病症,例如细胞增殖性疾病、癌症、免疫性疾病等。对比已报道的ALK抑制剂,本系列化合物具有更好的体内外活性和药效,在药物的用药剂量上也有明显优势,因此本申请的二苯氨基嘧啶及三嗪化合物具有很好的发展前景和市场潜力。
下面结合实施例,对本发明的具体实施方式作进一步详细描述。以下实施例用于说明本发明,但不用来限制本发明的范围。
一、化合物的制备
1、化合物IX的合成
将化合物XI进行取代反应,得到化合物IX化合物,其结果如表1所示:
表1 化合物IX结构
序号 | R2 | R4 | LC-MS(M+1) |
1 | CD3 | H | 191.0 |
2 | CD3 | CH3 | 205.0 |
3 | CD3 | F | 209.0 |
4 | CD3 | Cl | 225.0 |
5 | CD3 | CF3 | 259.0 |
6 | CD3 | CN | 216.0 |
7 | CD2CD3 | H | 207.1 |
8 | CD2CD3 | CH3 | 221.1 |
9 | CD2CD3 | Cl | 241.0 |
实施例1.化合物IX-1(R2=H,R4=CD3)的合成
在氮气保护下,将化合物(XI-1,R4=CD3)(2.3g,13.1mmol)加入到25mL的DMSO中,再向上述溶液中加入碳酸铯(20.8g,65.9mmol)。室温下滴加2.0mL氘代甲醇,升温至50℃反应1小时,TLC监测反应完全。然后将反应液倒入冰水中,用乙酸乙酯萃取两次,干燥有机相。蒸去有机溶剂后得到固体,然后用甲基叔丁基醚重结晶,得到化合物(IX-1)(2.0g,80%)。1H NMR(400MHz,DMSO-d6):δ=7.92(d,1H,J=6.8Hz),7.46(s,1H),7.30(d,1H,J=6.8Hz);LC-MS:m/z=191.0(M+1)。
实施例2.化合物IX-2(R2=Me,R4=CD3)的合成
在氮气保护下,将化合物(XI-2,R4=Me)(2.5g,13.1mmol)加入到25mL DMSO中,加入碳酸铯(20.8g,65.9mmol)至上述溶液中。室温下滴加氘代甲醇(2mL),升温至50℃
反应1小时,TLC监测反应完全,再将反应液倒入冰水混合物中,乙酸乙酯萃取两次,干燥有机相。然后过滤,蒸去有机溶剂后得到固体。然后用甲基叔丁基醚重结晶,得到化合物(IX-2)(2.2g,76.9%)。1H NMR(400MHz,DMSO-d6):δ=7.90(s,1H),7.52(s,1H),2.30(s,3H);LC-MS:m/z=205.0(M+1)。
实施例3.化合物IX-8(R2=Me,R4=CD2CD3)的合成
在氮气保护下,化合物(XI-8)(2.5g,13.1mmol)加入到25mL DMSO中,加入碳酸铯(20.8g,65.9mmol)至上述溶液中。室温下,滴加氘代乙醇(2mL),升温至50℃反应1h,TLC监测反应完全。反应液倒入冰水混合物中,乙酸乙酯萃取两次,干燥有机相后过滤,蒸去有机溶剂后得到固体。然后用甲基叔丁基醚重结晶,得到化合物(IX-8)(2.4g,83.0%)。1H NMR(400MHz,DMSO-d6):δ=7.92(s,1H),7.50(s,1H),2.30(s,3H):LC-MS:m/z=221.1(M+1)。
采用如实施例1-3所示的同样操作,得到一系列化合物(IX-1~9),其结构通过LC-MS质谱确认,结果见表1。
2、化合物VIII的合成
将化合物IX和化合物X进行Suzuki偶联反应,得到化合物VIII,反应路线如下所示:
其结果如表2所示:
表2.化合物VIII结构
序号 | R2 | R4 | LC-MS(M+1) |
1 | CD3 | H | 234.1 |
2 | CD3 | CH3 | 248.1 |
3 | CD3 | F | 252.1 |
4 | CD3 | Cl | 268.1 |
5 | CD3 | CF3 | 302.1 |
6 | CD3 | CN | 259.1 |
7 | CD2CD3 | H | 250.1 |
8 | CD2CD3 | CH3 | 264.1 |
9 | CD2CD3 | Cl | 284.1 |
实施例4.化合物VIII-2的合成(R2=CD3,R4=Me)
氮气保护下,将化合物(X)(1.47g,12mmol)加入到二氧六环和水(100mL/50mL)的混合溶剂中,依次将三-(二亚苄基丙酮)二钯(1g,1.09mmol),2-双环己基膦-2',6'-二甲氧基联苯(1.12g,2.72mmol),化合物(IX-2)(2.5g,10.9mmol)和磷酸钾(4.62g,21.8mmol)加入上述混合液中,氮气鼓泡15分钟,加热回流反应6h,TLC监测反应完全。室温下加入乙酸乙酯(200mL)稀释,1N氢氧化钠溶液洗涤。蒸去有机溶剂,过硅胶柱纯化后得化合物(VIII-2)(1.7g,68.8%)。1H NMR(400MHz,DMSO-d6):δ=8.60(d,2H,J=7.2Hz),8.06(d,2H,J=7.0Hz),7.96(s,1H),7.50(s,1H),2.30(s,3H);LC-MS:m/z=248.1(M+1)。
实施例5.化合物VIII-8的合成(R2=CD2CD3,R4=Me)
氮气保护下,化合物(X)(1.47g,12mmol)加入到二氧六环和水(100mL/50mL)的混合溶剂中,三-(二亚苄基丙酮)二钯[Pd2dba3](1g,1.09mmol),2-双环己基膦-2',6'-二甲氧基联苯(1.12g,2.72mmol),化合物(IX-8)(2.5g,10.9mmol)和磷酸钾(4.62g,21.8mmol)依次加入上述混合液中,氮气鼓泡15分钟,加热回流反应6h,TLC监测反应完全后,室温下加入乙酸乙酯(200mL)稀释,1N氢氧化钠溶液洗涤。然后分层,干燥,蒸去有机溶剂,过硅胶柱纯化后得化合物(VIII-8)(2.0g,62.8%)。1H NMR(400MHz,DMSO-d6):δ=8.62(d,2H,J=7.0Hz),8.02(d,2H,J=7.0Hz),7.92(s,1H),7.54(s,1H),2.32(s,3H);LC-MS:m/z=264.1(M+1)。
采用如实施例4-5所示的同样操作,得到一系列化合物(VIII-1~10),其结构通过LC-MS质谱确认,结果见表2。
关于化合物(IX-1)和哌嗪以及其他含氮杂环化合物的偶联反应,按照下述方法进行,结果如表3所示:
表3 化合物VIII’的结构
实施例6.化合物VIII’-11的合成
化合物VIII’-11的合成路线如下所示:
将化合物(IX-1)(3.8g,20mmol),Boc哌嗪(5.6g,30mmol)加入到50mLDMSO中,再加入三乙胺(3g,30mmol)。加热到70度,反应30小时。冷却到室温,加水(100mL)搅拌2小时得到沉淀,过滤得到化合物(VIII’-11)(4.80g,70%)。1H NMR(400MHz,DMSO-d6):δ=7.80(s,1H,J=7.0Hz),6.62(s,1H,J=7.0Hz),6.50(s,1H),3.32-3.42(m,8H),1.34(s,9H):LC-MS:m/z=341.2(M+1)。
采用如实施例6的同样操作,得到一系列化合物(VIII’-11~17),其结构通过LC-MS质谱确认,结果见表3。
3、化合物VII的合成
化合物VII的合成路线如下所示:
实施例7.化合物VII-2的合成(R4=Me,R2=CD3)
将化合物(VIII-2)(4.38g,16.1mmol),三氟乙酸(2.4ml,32.2mmol),PtO2(1.76g,40%)加入到乙酸(200mL)中,在氢气下反应36h。TLC监测反应完全后,过滤除去固体,蒸去母液中有机溶剂后,固体溶解于乙酸乙酯。然后,使用1NNaOH溶液洗涤至pH=10,有机相干燥、过滤、浓缩后得化合物(VII-2)(2.5g,70%)。1H NMR(400MHz,DMSO-d6):δ=9.50-8.04(br,1H),6.53(s,1H),6.44(s,1H),4.44(s,2H),3.03-2.96(m,2H),2.87-2.84(m,2H),2.83-2.80(m,1H),2.12(s,3H),1.78-1.72(m,4H):LC-MS:m/z=224.2(M+1)。
实施例8.化合物VII-8的合成(R4=Me,R2=CD2CD3)
化合物(VIII-8)(4.38g,16.1mmol),三氟乙酸(2.4ml,32.2mmol),PtO2(1.76g,40%)加入到乙酸(200mL)中,在氢气下反应36h,TLC监测反应完全后,过滤除去固体。蒸除溶剂后,固体溶解于乙酸乙酯,1N NaOH溶液洗涤至pH=10,有机相干燥、过滤、浓缩后得化合物(VII-8)(2.65g,68.8%)。1H NMR(400MHz,DMSO-d6):δ=9.52-8.00(br,1H),6.53(s,1H),6.48(s,1H),4.40(s,2H),3.00-2.92(m,2H),2.84-2.86(m,2H),2.80-2.82(m,1H),2.14(s,3H),1.78-1.70(m,4H);LC-MS:m/z=240.2(M+1)。
采用如实施例7-8的同样操作,得到一系列化合物(VII-1~9),其结构通过LC-MS质谱确认,结果见表4。
表4.化合物VII结构
序号 | R2 | R4 | LC-MS(M+1) |
1 | CD3 | H | 210.2 |
2 | CD3 | CH3 | 224.2 |
3 | CD3 | F | 228.2 |
4 | CD3 | Cl | 244.1 |
5 | CD3 | CF3 | 278.2 |
6 | CD3 | CN | 235.2 |
7 | CD2CD3 | H | 226.2 |
8 | CD2CD3 | CH3 | 240.2 |
9 | CD2CD3 | Cl | 260.2 |
关于含氮杂环化合物(VIII)的还原反应,按照下述方法进行,反应路线如下:
实施例9.化合物VII’-11的合成
化合物VII’-11的合成路线如下:
将化合物(VIII’-11)(6.8g,20mmol),10%Pd/C(0.6g,)加入到甲醇(100mL)中,在氢气下反应26h,TLC监测反应完全后,过滤除去固体,浓缩甲醇后得化合物(VII’-11)(5.7g,92%)。1H NMR(400MHz,DMSO-d6):δ=6.48(s,1H,J=7.0Hz),6.26(s,1H,J=7.0Hz),6.00(s,1H),3.30-3.40(m,8H),1.34(s,9H):LC-MS:m/z=311.2
(M+1)。
采用如实施例9的同样操作,得到一系列化合物(VII’-1~9),其结构通过LC-MS质谱确认,结果请见表5。
表5.含氮杂环化合物VII’结构
4、化合物IV的合成
化合物IV的合成路线如下所示:
实施例10.化合物IV-2的合成(R4=Me,R2=CD3)
将化合物(VII-2)(2.0g,9.0mmol),三乙胺(2.2ml,15.7mmol)溶解于二氯甲烷(100mL)中,降温至0℃,然后一次性加入二碳酸二叔丁酯(1.8g,9.0mmol),搅拌反应,TLC监测反应完全后,蒸去有机溶剂,过硅胶柱纯化得化合物(IV-2)(2g,69.0%)。1H NMR(400MHz,CD3OD)δ=7.61(s,1H),6.76(s,1H),4.22(d,J=13.2Hz,2H),2.90(m,3H),2.28(s,3H),1.73(d,J=12.2Hz,2H),1.54(d,J=11.4Hz,2H),1.52(s,9H);LC-MS:m/z=324.2(M+1)。
实施例11.化合物IV-8的合成(R4=Me,R2=CD2CD3)
化合物(VII-8)(2.0g,9.0mmol),三乙胺(2.2mL,15.7mmol)溶解于二氯甲烷(100mL)中,降温至0℃,加入二碳酸二叔丁酯(1.8g,9.0mmol),搅拌反应。TLC监测反应完全后,蒸去有机溶剂,过硅胶柱纯化得到化合物(IV-8)(2.5g,81.8%)。1H NMR(400MHz,CD3OD)δ=7.64(s,1H),6.72(s,1H),4.20(d,J=13.0Hz,2H),2.92(m,3H),2.24(s,3H),1.70(d,J=12.2Hz,2H),1.52(d,J=11.4Hz,2H),1.50(s,9H);LC-MS:m/z=340.2(M+1)。
采用如实施例10-11的同样操作,得到一系列化合物(IV-1~9),其结构通过LC-MS质谱确认,结果请见表6。
表6.化合物IV结构
序号 | R2 | R4 | LC-MS(M+1) |
1 | CD3 | H | 310.2 |
2 | CD3 | CH3 | 324.2 |
3 | CD3 | F | 328.2 |
4 | CD3 | Cl | 344.1 |
5 | CD3 | CF3 | 378.2 |
6 | CD3 | CN | 335.2 |
7 | CD2CD3 | H | 326.2 |
8 | CD2CD3 | CH3 | 340.2 |
9 | CD2CD3 | Cl | 360.2 |
5、化合物III的合成
将化合物V与嘧啶化合物VI进行偶联反应,得到化合物III,反应路线如下所示:
实施例12.化合物III-3的合成
在0℃氮气保护下,将NaH(1.51g,60%,37.64mmol)加入到DMF(50mL)和DMSO(5mL)中,在此温度下搅拌5分钟。然后向上述混合溶液中滴加化合物(V-3,R1=i-PrSO2)(5g,25.09mmol)的DMF/DMSO(18mL/2mL)溶液,保持温度0℃,搅拌45分钟,向上述混合液中滴加2,4,5-三氯嘧啶(III-3)(9.20g,50.18mmol)的DMF/DMSO(18mL/2mL)溶液。0℃搅拌45分钟,然后在室温下,搅拌2小时。TLC监测反应完全后,倒入冰水中,乙酸乙酯萃取两次。蒸去有机溶剂,过硅胶柱纯化后得化合物III-3(5.2g,60.6%)。1H NMR(400MHz,DMSO-d6):δ=9.81(s,1H),8.57(s,1H),8.32(d,J=8.3Hz,1H),7.96-7.82(m,2H),7.56-7.42(m,1H),3.61-3.46(m,1H),1.16(d,J=6.8Hz,6H);LC-MS:m/z=346.0(M+1)。
采用如实施例12的同样操作,得到一系列化合物(III-1~19),其结构通过LC-MS质谱确认,结果见表7。
表7.化合物III结构
6、化合物II的合成
在钯催化剂的催化下,将化合物III与化合物IV进行偶联反应,得到化合物II,反应路线如下所示:
实施例13.化合物II-3的合成
氮气保护下,将化合物(IV-2)(1.7g,4.8mmol),化合物(III-3)(1.69g,4.88mmol),4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(Xantphos)(280mg,0.49mmol),醋酸钯(55mg,0.25mmol),碳酸铯(4.77g,14.6mmol)加入到四氢呋喃中,加热至回流反应36h,TLC监测反应完全后,蒸去有机溶剂,过硅胶柱纯化得化合物(II-3)(2.1g,69.3%)。1H NMR(400MHz,DMSO-d6):δ=8.30(s,1H),8.27(d,J=7.2Hz,1H),7.84d,J=7.2Hz,1H),7.65(dd,J=7.2Hz,7.0Hz,1H),7.44(dd,J=7.2Hz,7.0Hz,1H),7.40(s,1H),6.80(s,1H),3.49-3.32(m,3H),3.10-2.91(m,3H),2.09(s,3H),1.89-1.77(m,4H),1.36(s,9H),1.13(d,6H):LC-MS:m/z=633.3(M+1)。
实施例14.化合物II-16的合成
氮气保护下,将化合物(IV-12)(1.5g,4.8mmol),化合物(III-3)(1.69g,4.88mmol),4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(Xantphos)(280mg,0.49mmol,0.1eq),醋酸钯(55mg,0.25mmol),碳酸铯(4.77g,14.6mmol)加入到四氢呋喃中,加热至回流反应40h,TLC监测反应完全后,蒸去有机溶剂,过硅胶柱纯化得化合物(II-16)(1.8g,72%)。
1H NMR(400MHz,DMSO-d6):δ=8.32(s,1H),8.24(d,J=7.2Hz,1H),7.82(d,J=7.2Hz,1H),7.65(dd,J=7.2Hz,7.0Hz,1H),7.40(dd,J=7.2Hz,7.0Hz,1H),7.32(d,J=6.8Hz,1H),6.80(s,1H),3.20-3.32(m,9H),1.36(s,9H),1.13(d,6H):LC-MS:m/z=620.2(M+1)。
采用如实施例13-14的同样操作,得到一系列化合物(II-1~43),其结构通过LC-MS质谱确认,结果见表8。
表8.化合物II结构
7、化合物I的合成
将带有Boc保护基团的化合物II进行脱保护反应,然后与氯化氢-乙醇溶液进行成盐反应,得到如式所示的目标化合物(I)的盐酸盐。若化合物II无保护基团,则不需要进行脱保护基反应,直接与氯化氢-乙醇溶液进行成盐反应即可。反应路线图如下所示:
实施例15.化合物I-3的合成
将化合物(II-3)(2.1g,3.3mmol)加入到二氯甲烷(10mL)和三氟乙酸(10mL)的溶液中,室温下搅拌2h,TLC监测反应完全后,蒸除有机溶剂,溶于二氯甲烷(100mL)中,用饱和碳酸钠溶液洗涤,干燥、过滤后浓缩得到自由胺。将自由胺产品溶于二氯甲烷(20mL)加入氯化氢/乙醇溶液(4M,10mL),室温下搅拌2h,有白色固体洗出,抽滤,烘干得化合
物(I-3)(1.8g,95.2%)。1H NMR(400MHz,DMSO-d6)δ=8.32(s,1H),8.27(d,J=7.2Hz,1H),7.88(d,J=7.2Hz,1H),7.67(dd,J=7.2Hz,7.0Hz,1H),7.45(dd,J=7.2Hz,7.0Hz,1H),7.42(s,1H),6.79(s,1H),3.49-3.32(m,3H),3.10-2.91(m,3H),2.09(s,3H),1.89-1.77(m,4H),1.13(d,6H):LC-MS:m/z=533.3(M+1)。
实施例16.化合物I-16的合成
将化合物(II-16)(1.7g,3.3mmol)加入到二氯甲烷(10mL)和三氟乙酸(10mL)的溶液中,室温下搅拌3h。TLC监测反应完全后,蒸去有机溶剂,然后溶于二氯甲烷(100mL)中,用饱和碳酸钠溶液洗涤,干燥、过滤后浓缩得到自由胺。将自由胺产品溶于二氯甲烷(20mL)加入氯化氢/乙醇溶液(4M,10mL),室温下搅拌2h,有白色固体洗出,抽滤,烘干得化合物(I-16)(1.4g,96%)。1H NMR(400MHz,DMSO-d6):δ=8.30(s,1H),8.20(d,J=7.2Hz,1H),7.82(d,J=7.2Hz,1H),7.62(dd,J=7.2Hz,7.0Hz,1H),7.42(dd,J=7.2Hz,7.0Hz,1H),7.36(d,J=6.8Hz,1H),6.80(s,1H),3.20-3.32(m,9H),1.13(d,6H):LC-MS:m/z=520.2(M+1)。
采用如实施例15-16的同样操作,得到一系列化合物(I-1~43),其结构通过质LC-MS谱确认,结果见表9。
表9.化合物I结构
二、生物活性测试
间变性淋巴瘤激酶(ALK)酶活性的抑制作用
体外激酶分析用Cisbio公司的HTRF kinEASE TK试剂盒,操作步骤参照试剂盒说明书,该方法在体外检测待测化合物对ALK酶活性的抑制作用。包括ALK野生型(Cat.PV3867,Invitrogen公司)、ALK L1196M(Cat.PV6168,Life technologies)、ALK F1174L(Cat.PV6160,Life technologies),具体操作步骤如下:
(1)首先使用配置好的1X kinase buffer分别配制2.5%的DMSO溶液(DMSO浓度过
高会对反应产生影响,控制DMSO的终浓度为1%),然后用酶对应的2.5%的DMSO溶液稀释待测化合物,化合物的筛选浓度为100nM,10nM和1nM。除对照孔外,向所用反应孔中加入4微升的稀释好的待测化合物溶液,向对照孔中加入4微升先前配制的ALK酶对应的2.5%的DMSO溶液。
(2)向所有反应孔中加入2微升事先配制好的ALK酶对应底物浓度的TK-biotin substrate溶液。
(3)向除阴性孔外的所有反应孔中加入2微升事先配制好的对应浓度的酶溶液,阴性孔用2微升酶对应1Xkinase buffer补足体积。用封板膜封板,混匀后室温孵育10分钟,让化合物和酶充分作用结合。
(4)向所有反应孔中加入2微升ALK酶对应浓度的ATP溶液来启动激酶反应,ALK的酶反应时间为60分钟。
(5)在激酶反应结束前5分钟开始配制ALK检测液。使用试剂盒中的detection buffer分别配制两种酶对应浓度的Streptavidin-XL665和TK antibody europium cryptate(1:100)检测液。
(6)待激酶反应结束后,向所有反应孔中加入5微升稀释好的的Streptavidin-XL665,混匀后立即加入稀释好的TK antibody europium cryptate检测液。
(7)封板混匀,室温反应1h后,用ENVISION(Perkinelmer)仪器检测荧光信号(320nm刺激,665nm,615nm发射)。通过全活性孔和背景信号孔计算出每个孔的抑制率,复孔取平均值,同时用专业的画图分析软件PRISM 5.0对每个待测化合物进行半数抑制活性(IC50)的拟合。
采用上述方法,各化合物对对ALK酶的抑制活性如表10所示。
表10 各化合物对ALK酶的抑制活性
IC50范围:+++表示1-10nM;++表示10-100nM;+表示100-1uM。
系列化合物在不同肿瘤细胞生长抑制试验(CCK8检测)
1、细胞株:
(1)Ba/F3小鼠IL-3依赖的原B淋巴细胞细胞株,RPMI 1640+10%FBS+10ng/ml Interleukin-3+1%Sodium Pyruvate;
(2)Karpas 299人T淋巴细胞瘤细胞株,RPMI 1640+10%FBS+1%Sodium Pyruvate;
(3)NCI-H2228人非小细胞肺癌细胞株,RPMI 1640+10%FBS+1%Sodium Pyruvate;
(4)NCI-H3122人肺癌细胞株,RPMI 1640+10%FBS+1%Sodium Pyruvate;
2、试剂与耗材:
CCK8试剂盒;抗肿瘤化合物;DMSO。
3、试验方法:
(1)细胞培养
a)收集对数生长期细胞,计数,用完全培养基重新悬浮细胞,
b)调整细胞浓度至合适浓度,接种96孔板,每孔接种100μl细胞悬液。
c)细胞在37℃,100%相对湿度,5%CO2培养箱中孵育24小时。
(2)相对抑制率实验
1)收集对数生长期细胞,计数,用完全培养基重新悬浮细胞,调整细胞浓度至合适浓度(依照细胞密度优化试验结果确定),接种96孔板,每孔加100μl细胞悬液。细胞在37℃,100%相对湿度,5%CO2培养箱中孵育24小时。
2)用培养基将待测化合物稀释至所设置的相应作用浓度,按25μl/孔加入细胞。化合物作用终浓度从10μM至0μM,4倍梯度稀释,共10个浓度点。
3)细胞置于37℃,100%相对湿度,5%CO2培养箱中孵育72小时。
4)吸弃培养基,加入含10%CCK-8的完全培养基置于37℃培养箱中孵育2-4小时。
5)轻轻震荡后在SpectraMax M5Microplate Reader上测定450nm波长处的吸光度,以650nm处吸光度作为参比,计算抑制率。
4、数据处理及结果
按下式计算药物对肿瘤细胞生长的抑制率:肿瘤细胞生长抑制率%=[(Ac-As)/(Ac-Ab)]×100%
As:样品的OA(细胞+CCK-8+待测化合物)
Ac:阴性对照的OA(细胞+CCK-8+DMSO)
Ab:阳性对照的OA(培养基+CCK-8+DMSO)
运用软件Graphpad Prism 5并采用计算公式log(inhibitor)vs.response进行IC50曲线
拟合并计算出IC50值。不同化合物对不同肿瘤细胞生长抑制活性(IC50)如表11所示。
表11 不同化合物对不同肿瘤细胞生长抑制活性(IC50)
体内药效学评价
SCID Beige小鼠,雌性,5~6周龄,体重18g±2g,购自北京华阜康生物科技股份有限公司,SPF级环境饲养。
NCI-H2228细胞培养于PRMI-1640,含10%胎牛血清FBS和1%丙酮酸钠。细胞置于5%CO2培养箱37℃培养。
细胞接种法建立肿瘤裸鼠皮下移植模型:收集对数生长期的肿瘤细胞,计数后重悬于PRMI-1640基础培养基,1:1加入Matrigel,调整细胞悬液浓度至6×107/ml。用1mL注射器(4号针头)在裸鼠右侧背部皮下接种肿瘤细胞,6×106/0.1mL/鼠。
在肿瘤体积达到200mm3左右时,将动物按随机区组法进行随机分组,使各组肿瘤差异小于均值的10%,每组8只共5组,分组当日记为Day 0,分组后立即给药,本发明化合物I-3和Ceritinib每天口服给药1次,连续给药14天后,观察7天。实验期间每周测定两次动物体重和肿瘤大小,每日观察记录临床症状,21天最后一次称量结束后,用CO2安乐死处死动物,取肿瘤,称量瘤重并拍照记录,计算肿瘤平均值。以考察在该实验条件下,受试物AMX6001对人肺癌NCI-H2228裸小鼠移植瘤的生长抑制作用。
当荷瘤小鼠肿瘤长到可测量的大小时,使用SPSS 17.0软件按照平均瘤体积均衡原则将
小鼠随机分成8组。化合物AMX6001以30,10,3mg/kg,每天灌胃给药;阳性对照药AMX6003以10mg/kg,每天灌胃给药,给药体积为0.1ml/10g。每天给药一次,连续给药14天,阴性对照组给等量溶剂(1%DMSO的生理盐水溶液),给药期和恢复期间,每周测量小鼠体重和瘤径2~3次。根据测量数据计算肿瘤体积和相对肿瘤体积,肿瘤体积(Tumor Volume,TV)的计算公式为:TV=1/2×a×b2,其中a、b分别表示肿瘤长径和短径。据测量结果计算出相对肿瘤体积(Relative tumor volume,RTV),计算公式为:RTV=Vt/V0,其中V0为试验开始时的肿瘤体积,Vt为每次测量的肿瘤体积。抗肿瘤活性的评价指标为相对肿瘤增值率T/C(%),计算公式如下:T/C(%)=TRTV/CRTV×100%,TRTV为治疗组RTV;CRTV为阴性对照组RTV,相对肿瘤生长抑制率(抑瘤率)%=(1-T/C)×100%,结果如表12所示。
表12 本发明化合物对NCI-H2228裸小鼠移植瘤的治疗作用
以上所述仅是本发明的优选实施方式,并不用于限制本发明,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明技术原理的前提下,还可以做出若干改进和变型,这些改进和变型也应视为本发明的保护范围。
Claims (10)
- 一种如式I所示的二苯氨基嘧啶及三嗪化合物,或其药学上可接受的盐、立体异构体、水合物或溶剂合物:其中:A为C或N;X、Y独立地选自氢、卤素、氰基、三氟甲基、烷氧基、烷基、芳环基、烯基、炔基或硝基;或者,X和Y与它们所连接的原子一起形成苯环或芳香杂环,所述芳香杂环含有氧、硫和氮杂原子中的一种或几种;R2为CD3或CD2CD3;R4选自氢、甲基、三氟甲基、氰基或卤素;R5选自氢、烷基、取代和未取代的苯基、烯丙基或炔丙基;R6、R7独立地选自氢、烷基、取代和未取代的苯基、烯丙基、炔丙基;或者,R6和R7与它们所连接的N原子一起形成取代或未取代的杂环烷基,所述杂环烷基含有氧、硫、氮、亚砜基和砜基中的一种或几种。
- 一种药物组合物,其特征在于:包括权利要求1-3中任一项所述的二苯氨基嘧啶及三嗪化合物,或其药学上可接受的盐、立体异构体、水合物或溶剂合物,以及药学上可接受的载体或赋形剂。
- 权利要求1-3中任一项所述的二苯氨基嘧啶及三嗪化合物,或其药学上可接受的盐、立体异构体、水合物或溶剂合物在制备药物中的用途,所述药物为ALK酪氨酸激酶抑制剂,或用于治疗和/或预防受益于ALK酪氨酸激酶活性抑制的疾病或病症。
- 根据权利要求5所述的用途,其特征在于:所述疾病或病症为癌症、细胞增殖性疾病、免疫性疾病或炎症、感染、器官移植、病毒性疾病、心血管疾病或代谢性疾病。
- 根据权利要求6所述的用途,其特征在于:所述癌症为非小细胞肺癌、白血病或淋巴瘤。
- 根据权利要求6所述的用途,其特征在于:所述免疫性疾病或炎症为类风湿性关节炎、骨关节炎、类风湿性脊椎炎、痛风、哮喘、支气管炎、鼻炎、慢性阻塞性肺病或囊性纤维化病。
- 根据权利要求5所述的用途,其特征在于:所述药物单独给药或与其他治疗药物联合用药。
- 根据权利要求5-9中任一项所述的用途,其特征在于:所述药物经口服、胃肠道外、肺部或皮肤给药。
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EP17833292.0A EP3466943B1 (en) | 2016-07-25 | 2017-05-04 | Diphenylaminopyrimidine and triazine compound, and pharmaceutical composition and use thereof |
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CN108689994A (zh) * | 2017-07-01 | 2018-10-23 | 浙江同源康医药股份有限公司 | 用作alk激酶抑制剂的化合物及其应用 |
CN110305161A (zh) * | 2018-03-20 | 2019-10-08 | 暨南大学 | 2-氨基嘧啶类化合物及其应用 |
WO2019223777A1 (zh) * | 2018-05-24 | 2019-11-28 | 北京赛特明强医药科技有限公司 | 一种含有芳胺基取代的吡咯并嘧啶类化合物、制备方法及其应用 |
CN110526941A (zh) * | 2018-05-24 | 2019-12-03 | 北京赛特明强医药科技有限公司 | 一种含有间氯苯胺类取代基的吡咯并嘧啶类化合物、制备方法及其应用 |
CN111825719A (zh) * | 2019-04-15 | 2020-10-27 | 北京赛特明强医药科技有限公司 | 一种含有芳胺基取代的吡咯并嘧啶类化合物、制备方法及其应用 |
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CN114621206B (zh) * | 2022-03-24 | 2023-11-24 | 安徽医科大学 | 一种5-取代的嘧啶二胺类衍生物及其制备方法与应用 |
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US10647694B2 (en) | 2020-05-12 |
US20190256493A1 (en) | 2019-08-22 |
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