CN104557939B - The hydrochloride of Pyrrolopyrazine compound and its application - Google Patents

The hydrochloride of Pyrrolopyrazine compound and its application Download PDF

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CN104557939B
CN104557939B CN201410567613.3A CN201410567613A CN104557939B CN 104557939 B CN104557939 B CN 104557939B CN 201410567613 A CN201410567613 A CN 201410567613A CN 104557939 B CN104557939 B CN 104557939B
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alkyl
compound
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inhibitor
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CN104557939A (en
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王勇
赵立文
谢同
沙向阳
苏小川
张波
叶嘉伟
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Nanjing Shenghe pharmaceutical research and Development Co., Ltd
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Nanjing Sanhome Pharmaceutical Co Ltd
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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
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    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

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Abstract

The invention belongs to chemical medicines, it is related to hydrochloride and its application of a kind of Pyrrolopyrazine compound, more particularly to a kind of Pyrrolopyrazine compound with BCR-ABL kinase inhibiting activities, and the pharmaceutical composition containing the compound and application of the compound or composition in medicine preparation.Pyrrolopyrazine compound provided by the invention all has the inhibiting effect of highly significant, while showing good stability, dissolubility and oral administration biaavailability to kinds of tumor cells, including T315I mutation, drug resistant leukaemia cell.

Description

The hydrochloride of Pyrrolopyrazine compound and its application
Technical field
The invention belongs to chemical medicines, and in particular to a kind of pyrrolo- pyrrole with BCR-ABL kinase inhibiting activities Piperazine compound, and the pharmaceutical composition containing the compound and application of the compound or composition in medicine preparation.
Background technology
Protein tyrosine kinase (PTKs), which is one kind, can be catalyzed γ-phosphoric acid on ATP and be transferred on protein-tyrosine residue Kinases, by be catalyzed multiple protein tyrosine residue on phenolic hydroxyl group occur phosphorylation, and then activate functional protein effect Protein enzyme system.In occupation of highly important status in the signal transduction pathway of protein tyrosine kinase (PTKs) in the cell, Adjust a series of physiological and biochemical procedures such as cell growth, differentiation, death.The unconventionality expression of protein tyrosine kinase can cause carefully Born of the same parents are proliferated to adjust and get muddled, and then lead oncogenic generation.In addition, the unconventionality expression of protein tyrosine kinase also with tumour Invasion and transfer, the chemotherapy drug resistance of tumor neovasculature generation, tumour are closely related.Tyrosine kinase inhibitor can be used as The competitive inhibitor that atriphos (ATP) is combined with tyrosine kinase, competitive binding tyrosine kinase block tyrosine The activity of kinases inhibits cell Proliferation, has had several tyrosine protein kinase inhibitors to be successfully obtained exploitation.
In chronic myelocytic leukemia (CML) patient, No. 22 chromosome long arm transpositions to No. 9 chromosomes form Philadelphia dye Colour solid, and BCR genes and abl gene is caused to merge to form BCR-ABL fusions, BCR-ABL protein tyrosine kinase is expressed, The effects that passing through phosphorylation in cell signalling and conversion, promotes the unlimited hyperplasia of CML maturation granulocytes.BCR-ABL is just It is not expressed in normal cell, has become the ideal medicament target for the treatment of CML.Currently, BCR-ABL tyrosine kinase Have become the first-line treatment drug of most of chronic myelocytic leukemias.
Imatinib is the protein tyrosine kinase inhibitor of first molecular targeted therapy, and inside and outside can be in cellular water Flat upper inhibition BCR-ABL tyrosine kinase, selective depression BCR-ABL positive cell lines cell and Philadelphia Chromosome Positive (Ph+) increasing of the fresh human leukemia cells of chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL) patient It grows, induces its apoptosis.The exploitation of Imatinib and Clinical practice open the new era of tumor cells targeting, but take for a long time Imatinib will produce drug resistance, lead to disease relapse.With the extensive use of Imatinib clinically, resistance problems day Benefit is prominent.The main reason for acquired tolerance is since the point mutation of BCR-ABL causes Imatinib that cannot be combined with BCR-ABL And generate.And, it has been found that hundreds of BCR-ABL point mutation is related to imatinib-resistant, wherein 15~20% her horse For Buddhist nun intolerant patient, there are T315I mutation.
The appearance of imatinib-resistant has evoked the research and development upsurge of tyrosine kinase inhibitor of new generation, to develop Go out and is more preferably used to treat leukaemia, such as the new drug of drug resistance or not drug resistant each phase CML, Ph+ALL.
Compound 3- ((1H- Bi Kabings [2,3-b]Pyrazine -5- bases) acetenyl) -4- methyl-N-[4- ((4- methyl piperazines- 1- yls) methyl) -3- San Fujiajibenjis ]Benzamide has the knot of the following formula A as described in CN 201210493364.9 Structure：
CN 201210493364.9 reports 3- ((1H- Bi Kabings [2,3-b]Pyrazine -5- bases) acetenyl) -4- methyl - N-[4- ((4- methylpiperazine-1-yls) methyl) -3- San Fujiajibenjis ]Benzamide has good suppression to a variety of cancer cells System activity, can be used for treatment and/or pre- preventing tumor.But, CN 201210493364.9 does not disclose 3- ((1H- pyrrolo-es;2, 3-b]Pyrazine -5- bases) acetenyl) -4- methyl-N-[4- ((4- methylpiperazine-1-yls) methyl) -3- San Fujiajibenjis ]Benzene first Any specific salt of amide.
Invention content
It is an object of the present invention to provide compound the 3- ((1H- of the BCR-ABL kinase inhibitory effects with wide spectrum Bi Kabing [2,3-b]Pyrazine -5- bases) acetenyl) -4- methyl-N-[4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls Ben Ji ]Benzamide hydrochloride salt or its isomers, solvate, crystallization or prodrug.
It is another object of the present invention to provide prepare 3- ((1H- Bi Kabings [2,3-b]Pyrazine -5- bases) acetenyl) - 4- methyl-N-[4- ((4- methylpiperazine-1-yls) methyl) -3- San Fujiajibenjis ]Benzamide hydrochloride salt or its isomers, The method of solvate, crystallization or prodrug.
It is yet a further object of the present invention to provide contain 3- ((1H- Bi Kabings [2,3-b]Pyrazine -5- bases) acetenyl) - 4- methyl-N-[4- ((4- methylpiperazine-1-yls) methyl) -3- San Fujiajibenjis ]Benzamide hydrochloride salt or its isomers, The pharmaceutical composition of solvate, crystallization or prodrug and pharmaceutically acceptable carrier, and include 3- ((1H- Bi Kabings [2, 3-b]Pyrazine -5- bases) acetenyl) -4- methyl-N-[4- ((4- methylpiperazine-1-yls) methyl) -3- San Fujiajibenjis ]Benzene first Amide hydrochloride or its isomers, solvate, crystallization or prodrug and one or more protein tyrosine kinase inhibitors Composition.
The present invention's further an object is that provide 3- ((1H- Bi Kabings [2,3-b]Pyrazine -5- bases) acetenyl) -4- first Base-N-[4- ((4- methylpiperazine-1-yls) methyl) -3- San Fujiajibenjis ]Benzamide hydrochloride salt or its isomers, solvent Close object, crystallization or prodrug or its medicine composite for curing and/or pre- preventing tumor method and they preparing for treating And/or the purposes in the drug of pre- preventing tumor.
For above-mentioned purpose, the present invention provides following technical scheme：
In a first aspect, the present invention provides compound or its pharmaceutically acceptable salt, isomers, solvate, crystallization of Formulas I Or prodrug,
Wherein：
X is selected from N and C (R5), wherein R5Selected from hydrogen, halogen, C1-6Alkyl, halogenated C1-6Alkyl；
Y is selected from N and C (R6), wherein R6Selected from hydrogen, halogen, C1-6Alkyl, halogenated C1-6Alkyl；
R1Selected from hydrogen, alkyl, alkoxy, halogenated alkyl, halogenated alkoxy ,-OH ,-NH2, halogen and CN；
R2Selected from hydrogen, alkyl, alkoxy, halogenated alkyl, halogenated alkoxy ,-OH ,-NH2, halogen and CN；
W is selected from C1-6Alkylidene ,-C (O)-, with R4It forms 4-8 members naphthenic base or is not present；
R3Selected from substituted or unsubstituted five yuan, hexa-atomic, seven yuan and eight member heterocyclic ring containing nitrogen bases；
R4Form selected from hydrogen, alkyl, halogenated alkyl or together with W 4-8 member naphthenic base.
In some preferred embodiments, the compound of the present invention be Formulas I compound and its pharmaceutically acceptable salt, Isomers, solvate, crystallization or prodrug, wherein：
X is selected from N and C (R5), wherein R5Selected from hydrogen, fluorine, chlorine, bromine, C1-4Alkyl, halogenated C1-4Alkyl；
Y is selected from N and C (R6), wherein R6Selected from hydrogen, fluorine, chlorine, bromine, C1-4Alkyl, halogenated C1-4Alkyl；
R1Selected from hydrogen, C1-4Alkyl, C1-4Alkoxy, halogenated C1-4Alkyl, halogenated C1-4Alkoxy ,-OH ,-NH2, fluorine, chlorine, Bromine and CN；
R2Selected from hydrogen, C1-4Alkyl, C1-4Alkoxy, halogenated C1-4Alkyl, halogenated C1-4Alkoxy ,-OH ,-NH2, fluorine, chlorine, bromine And CN；
W is selected from C1-4Alkylidene ,-C (O)-, with R4It forms 4-8 members naphthenic base or is not present；
R3Selected from piperazinyl, pyridyl group, azabicycloalkyl, imidazole radicals, pyrazolyl, pyrrole radicals, triazolyl, pyridazinyl, Pyrimidine radicals, pyrazinyl, piperidyl, triazine radical, or substitution piperazinyl, pyridyl group, azabicycloalkyl, imidazole radicals, pyrazolyl, Pyrrole radicals, triazolyl, pyridazinyl, pyrimidine radicals, pyrazinyl, piperidyl, triazine radical, wherein the substitution is selected from alkyl, hydroxyl, hydroxyl Alkyl, alkoxy, amino, alkyl monosubstituted amino, double alkyl aminos, acylamino-, alkyl amido, acrylamido, heteroaryl acyl The alkoxy that amino, halogen, the alkyl of halogen substitution, halogen replace, the preferably described substituent group are selected from C1-6Alkyl, hydroxyl, hydroxyl C1-6Alkyl, C1-6Alkoxy, amino, list C1-6Alkyl amino, double C1-6Alkyl amino, acylamino-, C1-6Alkyl amido, aryl The C that acylamino-, heteroarylamido, halogen, halogen replace1-6The C that alkyl, halogen replace1-6Alkoxy.
R4Selected from hydrogen, C1-6Alkyl, halogenated C1-6Alkyl or constituted together with W pentamethylene base, cyclobutane base, cyclohexyl, Cycloheptyl alkyl.
It is highly preferred that the compound of the present invention includes the compound and its pharmaceutically acceptable salt, isomers, solvent of Formulas I Object, crystallization or prodrug are closed, wherein：
X is selected from N and C (R5), wherein R5Selected from hydrogen, fluorine, chlorine, bromine, C1-3Alkyl, halogenated C1-3Alkyl；
Y is selected from N and C (R6), wherein R6Selected from hydrogen, fluorine, chlorine, bromine, C1-3Alkyl, halogenated C1-3Alkyl；
R1Selected from hydrogen, C1-3Alkyl, C1-3Alkoxy, halogenated C1-3Alkyl, halogenated C1-3Alkoxy ,-OH ,-NH2, fluorine, chlorine, bromine And CN；
R2Selected from hydrogen, C1-3Alkyl, C1-3Alkoxy, halogenated C1-3Alkyl, halogenated C1-3Alkoxy ,-OH ,-NH2, fluorine, chlorine, bromine And CN；
W is selected from C1-3Alkylidene (such as-CH2,-CH2-CH2) ,-C (O)-, with R4It forms pentamethylene base or is not present；
R3Selected from piperazinyl, piperidin-4-yl, diazabicyclo octyl such as 3,8- Er Danzashuanhuans [3.2.1]Octane Base, the piperazinyl, piperidin-4-yl, diazabicyclo octyl can be by one or more C1-6Alkyl, C1-6Alkoxy takes Generation, such as by substitutions such as one or more methyl, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl or propoxyl group；
R4Selected from hydrogen, C1-4Alkyl, halogenated C1-4Alkyl constitutes pentamethylene base together with W.
In some embodiments of above-mentioned compound of formula I, wherein X is N, Y N.
In some embodiments of above-mentioned compound of formula I, wherein X is N, and Y is C (R6), the R6Selected from hydrogen, halogen, C1-6Alkyl, halogenated C1-6Alkyl, preferably R6Selected from hydrogen, fluorine, chlorine, bromine, C1-4Alkyl, halogenated C1-4Alkyl, more preferably R6It is selected from Hydrogen, fluorine, chlorine, bromine, C1-3Alkyl, halogenated C1-3Alkyl.
In some embodiments of above-mentioned compound of formula I, wherein X is C (R5), Y N, the R5Selected from hydrogen, halogen, C1-6Alkyl, halogenated C1-6Alkyl, preferably R5Selected from hydrogen, fluorine, chlorine, bromine, C1-4Alkyl, halogenated C1-4Alkyl, more preferably R5It is selected from Hydrogen, fluorine, chlorine, bromine, C1-3Alkyl, halogenated C1-3Alkyl.
In some embodiments of above-mentioned compound of formula I, wherein X is C (R5), Y is C (R6), the R5And R6Respectively Independently selected from hydrogen, halogen, C1-6Alkyl, halogenated C1-6Alkyl, preferably R5And R6Be each independently selected from hydrogen, fluorine, chlorine, bromine, C1-4Alkyl, halogenated C1-4Alkyl, more preferably R5And R6It is each independently selected from hydrogen, fluorine, chlorine, bromine, C1-3Alkyl, halogenated C1-3Alkane Base.
Preferably, the present invention provides compound or its pharmaceutically acceptable salt, isomers, solvate, crystallization of Formulas I a Or prodrug,
Wherein：
X is selected from N and C (R5), wherein R5Selected from hydrogen, halogen, C1-6Alkyl, halogenated C1-6Alkyl；
Y is selected from N and C (R6), wherein R6Selected from hydrogen, halogen, C1-6Alkyl, halogenated C1-6Alkyl；
R1Selected from hydrogen, alkyl, alkoxy, halogenated alkyl, halogenated alkoxy ,-OH ,-NH2, halogen and CN；
R2Selected from hydrogen, alkyl, alkoxy, halogenated alkyl, halogenated alkoxy ,-OH ,-NH2, halogen and CN；
W is selected from C1-6Alkylidene ,-C (O)-are not present；
R3Selected from substituted or unsubstituted five yuan, hexa-atomic, seven yuan and eight member heterocyclic ring containing nitrogen bases, preferably R3For piperazinyl, pyrrole Piperidinyl, azabicycloalkyl, imidazole radicals, pyrazolyl, pyrrole radicals, triazolyl, pyridazinyl, pyrimidine radicals, pyrazinyl, piperidyl, three Piperazine base, or it is the piperazinyl of substitution, pyridyl group, azabicycloalkyl, imidazole radicals, pyrazolyl, pyrrole radicals, triazolyl, pyridazinyl, phonetic Piperidinyl, pyrazinyl, piperidyl, triazine radical, wherein the substituent group is selected from C1-6Alkyl, hydroxyl, hydroxyl C1-6Alkyl, C1-6Alkoxy, Amino, list C1-6Alkyl amino, double C1-6Alkyl amino, acylamino-, C1-6Alkyl amido, acrylamido, heteroaryl acyl ammonia The C that base, halogen, halogen replace1-6The C that alkyl, halogen replace1-6Alkoxy, more preferably R3For piperazinyl, piperidin-4-yl, two Azabicycloalkyl such as 3,8- Er Danzashuanhuans [3.2.1]Octyl, or by one or more C1-6Alkyl, C1-6Alkoxy replaces Piperazinyl, piperidin-4-yl, diazabicyclo alkyl, such as R3For 4- methylpiperazine-1-yls, piperidin-4-yl, 1- methyl piperazines Pyridine -4- bases, 3,8- Er Danzashuanhuans [3.2.1]Octane -8- bases, 1- methyl -3,8- Er Danzashuanhuans [3.2.1]Octane -8- bases；
R4Selected from hydrogen, C1-6Alkyl, halogenated C1-6Alkyl.
Preferably, according to the present invention, in some embodiments, in Formulas I, Ia, R1Selected from hydrogen, alkyl, alkoxy, halogen Substituted alkyl, halogen and CN, especially R1Selected from hydrogen, C1-6Alkyl, C1-6Alkoxy, halogenated C1-6Alkyl, halogen and CN.
Preferably, according to the present invention, in some embodiments, in Formulas I, Ia, R2Selected from hydrogen, alkyl, halogenated alkyl, Halogen and CN, especially R2Selected from hydrogen, C1-6Alkyl, halogenated C1-6Alkyl, halogen and CN.
Preferably, according to the present invention, in some embodiments, in Formulas I, Ia, R3Selected from 4- methylpiperazine-1-yls, Piperidin-4-yl, 1- methyl piperidine -4- bases, 3,8- Er Danzashuanhuans [3.2.1]Octane -8- bases, 1- methyl -3,8- diazas are double Huan [3.2.1]Octane -8- bases.
Preferably, according to the present invention, in some embodiments, in Formulas I, Ia, R4Selected from methyl and trifluoromethyl.
Preferably, according to the present invention, in some embodiments, in Formulas I, Ia, W and R4Pentamethylene base is constituted together.
Preferably, according to the present invention, in some embodiments, in Formulas I, Ia, R5Selected from hydrogen, halogen.
Preferably, according to the present invention, in some embodiments, in Formulas I, Ia, R6Selected from hydrogen, halogen.
Preferably, according to the present invention, in some embodiments, in Formulas I, Ia, R1Selected from hydrogen, methyl, trifluoromethyl, Methoxyl group, ethyoxyl, propoxyl group or isopropoxy.
Preferably, according to the present invention, in some embodiments, in Formulas I, Ia, R2Selected from hydrogen, methyl, ethyl, propyl And isopropyl.
Preferably, according to the present invention, in some embodiments, in Formulas I, Ia, R5Selected from hydrogen, fluorine.
Preferably, according to the present invention, in some embodiments, in Formulas I, Ia, R6Selected from hydrogen, fluorine.
In a specific embodiment, the present invention provides the pharmaceutically acceptable salt or its isomery of the compound of Formulas I a Body, solvate, crystallization or prodrug,
Wherein：
X is C (R5), wherein R5For hydrogen；
Y is C (R6), wherein R6For hydrogen；
R1For hydrogen；
R2For methyl；
W is-CH2-；
R3For 4- methylpiperazine-1-yls；
R4For trifluoromethyl；
Wherein the salt is the pharmaceutically acceptable salt formed with hydrochloric acid, i.e. 3- ((1H- pyrrolo-es;2,3-b]Pyrrole Piperazine -5- bases) acetenyl) -4- methyl-N-[4- ((4- methylpiperazine-1-yls) methyl) -3- San Fujiajibenjis ]Benzamide monohydrochloride Hydrochlorate.
In a specific embodiment, the present invention provides 3- ((1H- Bi Kabings [2,3-b]Pyrazine -5- bases) acetylene Base) -4- methyl-N-[4- ((4- methylpiperazine-1-yls) methyl) -3- San Fujiajibenjis ]Benzamide hydrochloride salt or its isomery Body, solvate, crystallization or prodrug, wherein the hydrochloride has the following structure：
On the other hand, the present invention provides the preparation method of the general formula compound of the present invention.The preparation method of the compound of Formulas I Include the following steps：
(1) preparation of the intermediate of formula 5：
A) intermediate of formula 3 is obtained by the reaction in the compound of the compound of formula 1 and formula 2；
B) intermediate of formula 4 is obtained by the reaction in the intermediate Yu trimethylsilyl acetylene of formula 3；
C) intermediate of formula 4 sloughs trimethylsilyl and obtains the intermediate of formula 5；
(2) preparation of the compound of Formulas I：
D) intermediate of formula 5 and the intermediate reaction of formula 6 obtain the compound of Formulas I.
Wherein, R1、R2、R3、R4, W, X, Y have Formulas I in meaning, M be selected from chlorine, bromine, iodine.
In a specific embodiment, the present invention provide the present invention as following formula I compound, i.e. 3- ((1H- pyrroles Cough up simultaneously [2,3-b]Pyrazine -5- bases) acetenyl) -4- methyl-N-[4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethylbenzenes Ji ]Benzamide hydrochloride salt or its isomers, solvate, crystallization or prodrug preparation method include the following steps：
(1) preparation of the intermediate of formula 5：
A) intermediate of formula 3 is obtained by the reaction in the compound of the compound of formula 1 and formula 2；
B) intermediate of formula 4 is obtained by the reaction in the intermediate Yu trimethylsilyl acetylene of formula 3；
C) intermediate of formula 4 sloughs trimethylsilyl and obtains the intermediate of formula 5；
(2) preparation of the compound of Formulas I：
D) intermediate of formula 5 and the intermediate reaction of formula 6 obtain the compound of Formulas I.
Wherein, R1For hydrogen, R2For methyl, R3For 4- methylpiperazine-1-yls, R4For trifluoromethyl, W is-CH2, X C, Y are C, M are selected from chlorine, bromine, iodine.
The third aspect, the present invention provide pharmaceutical composition, it includes the compound of the present invention or its pharmaceutically acceptable salt, Isomers, solvate, crystallization or prodrug.
In some embodiments, the present invention provides pharmaceutical composition, and it includes the compound of the present invention, isomers, molten Object, crystallization or prodrug are closed in agent, also include one or more selected from following composition：Tyrosine protein enzyme inhibitor, EGFR inhibit Agent, VEGFR inhibitor, BCR-ABL inhibitor, c-kit inhibitor, c-Met inhibitor, Raf inhibitor, mek inhibitor, group egg White deacetylase inhibitor, VEGF antibody, EGF antibody, HIV kinases inhibitors, HMG-CoA reductase inhibitor etc..
In some specific embodiments, the present invention provides pharmaceutical composition, and it includes 3- ((1H- Bi Kabings [2,3- b]Pyrazine -5- bases) acetenyl) -4- methyl-N-[4- ((4- methylpiperazine-1-yls) methyl) -3- San Fujiajibenjis ]Benzoyl The pharmaceutical composition of amine hydrochlorate or its isomers, solvate, crystallization or prodrug and pharmaceutically acceptable carrier.
In other specific embodiments, the present invention provides pharmaceutical composition, and it includes 3- ((1H- Bi Kabings [2, 3-b]Pyrazine -5- bases) acetenyl) -4- methyl-N-[4- ((4- methylpiperazine-1-yls) methyl) -3- San Fujiajibenjis ]Benzene first Amide hydrochloride or its isomers, solvate, crystallization or prodrug also include one or more selected from following composition：Junket ammonia Pepsin inhibitor, EGFR inhibitor, VEGFR inhibitor, BCR-ABL inhibitor, c-kit inhibitor, c-Met inhibitor, Raf inhibitor, mek inhibitor, inhibitors of histone deacetylase, VEGF antibody, EGF antibody, HIV kinases inhibitors, HMG-CoA reductase inhibitor etc..
Can by the compound of the present invention, isomers, solvate, crystallization or prodrug and pharmaceutically acceptable carrier, Diluent or excipient are prepared by mixing into pharmaceutical preparation, to be suitable for oral or parenteral.In some specific embodiment party In case, by 3- ((1H- Bi Kabings [2,3-b]Pyrazine -5- bases) acetenyl) -4- methyl-N-[4- ((4- methylpiperazine-1-yls) first Base) -3- San Fujiajibenjis ]Benzamide hydrochloride salt or its isomers, solvate, crystallization or prodrug with it is pharmaceutically acceptable Carrier, diluent or excipient be prepared by mixing into pharmaceutical preparation, to be suitable for oral or parenteral.Medication packet It includes, but is not limited to that intradermal, intramuscular, peritonaeum is interior, intravenous, subcutaneous, intranasal and peroral route.The preparation can pass through any way Diameter is applied, such as by being transfused or injecting, the way absorbed by transepithelial or mucocutaneous (such as oral mucosa or rectum etc.) Diameter is applied.Administration can be whole body or local.The example of oral administration preparation includes solid or liquid dosage form, it is specific and Speech, including tablet, pill, granula, pulvis, capsule, syrup, emulsion, suspension etc..The preparation can be by known in the art Method prepare, and include the conventional use of carrier of field of pharmaceutical preparations, diluent or excipient.
Fourth aspect, the present invention provide the compound of the present invention, isomers, solvate, crystallization or prodrug or the present invention Medicine composite for curing and/or pre- preventing tumor method and prepare prevent and/or tumor in application, including Easily sent out to tumour crowd or tumor patient apply the compound of the present invention, isomers, solvate, crystallization or prodrug or comprising The pharmaceutical composition of the compound of the present invention, isomers, solvate, crystallization or prodrug, effectively to reduce Tumor incidence, prolong Bearing tumor patient vitals.
In some specific embodiments, the present invention provides 3- ((1H- Bi Kabings [2,3-b]Pyrazine -5- bases) acetylene Base) -4- methyl-N-[4- ((4- methylpiperazine-1-yls) methyl) -3- San Fujiajibenjis ]Benzamide hydrochloride salt or its is different Structure body, solvate, crystallization or prodrug include 3- ((1H- Bi Kabings [2,3-b]Pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- San Fujiajibenjis ]Benzamide hydrochloride salt or its isomers, solvate, The method of the medicine composite for curing or pre- preventing tumor of crystallization or prodrug and the application in preparing prevention or tumor, 3- ((1H- Bi Kabings &#91 are applied including easily sending out crowd or tumor patient to tumour;2,3-b]Pyrazine -5- bases) acetenyl) -4- methyl - N-[4- ((4- methylpiperazine-1-yls) methyl) -3- San Fujiajibenjis ]Benzamide hydrochloride salt or its isomers, solvent close Object, crystallization or prodrug or pharmaceutical composition containing them, effectively to reduce Tumor incidence, extend tumor patient life. In some embodiments, 3- ((1H- Bi Kabings &#91 provided by the invention;2,3-b]Pyrazine -5- bases) acetenyl) -4- methyl-N-[4- ((4- methylpiperazine-1-yls) methyl) -3- San Fujiajibenjis ]Benzamide hydrochloride salt or its isomers, solvate, crystallization Or prodrug or its pharmaceutical composition are used to prepare treatment and/or prevent cancer drug, the cancer includes solid tumor and various Lymphatic cells tumour.
It was found by the inventors of the present invention that using 3- ((the 1H- Bi Kabings &#91 of the present invention;2,3-b]Pyrazine -5- bases) acetenyl) - 4- methyl-N-[4- ((4- methylpiperazine-1-yls) methyl) -3- San Fujiajibenjis ]On the one hand benzamide hydrochloride salt dissolves Property significantly improved, good oral absorptivity can be played, be that can guarantee enough blood concentration with less amount, in turn Improve its internal drug effect；On the other hand, stability is improved, and especially under illumination condition, has significant stability Advantage.3- ((the 1H- Bi Kabings &#91 of the present invention;2,3-b]Pyrazine -5- bases) acetenyl) -4- methyl-N-[4- ((4- methyl piperazines- 1- yls) methyl) -3- San Fujiajibenjis ]Benzamide hydrochloride salt or its isomers, solvate, crystallization or prodrug are dosage form Research provides better choice.
Term explanation
" alkyl " of the present invention refers to linear or branched saturated hydrocarbon base, preferably C1-6Alkyl, further preferably C1-3 Alkyl, suitable C1-3Alkyl is methyl, ethyl, propyl, isopropyl.
" alkoxy " of the present invention refers to alkyl-O-, preferably C1-6Alkyl-O-, further preferably C1-3Alkyl-O-, Suitable C1-3Alkyl-O- is methoxyl group, ethyoxyl, propoxyl group, isopropoxy.
" halogen " of the present invention refers to fluorine, chlorine, bromine, iodine, preferably fluorine, chlorine.
" halogenated alkyl " of the present invention refers to the alkyl at least replaced by a halogen, preferably halogenated C1-6Alkyl, into one Step is preferably halogenated C1-3Alkyl, suitable halogenated C1-3Alkyl is chloromethyl, methyl fluoride, dichloromethyl, difluoromethyl, three chloromethanes Base, trifluoromethyl, chloroethyl, fluoro ethyl, Dichloroethyl, bis-fluoro ethyls, trichloroethyl, trifluoroethyl.
" halogenated alkoxy " of the present invention refers to the alkoxy at least replaced by a halogen, preferably at least by a halogen The C of element substitution1-6Alkoxy, further preferably halogenated C1-3Alkoxy, suitable halogenated C1-3Alkoxy is chloromethane epoxide, fluorine Methoxyl group, dichloro methoxyl group, difluoro-methoxy, trichloromethoxy, trifluoromethoxy；Two chloroethoxies, difluoroethoxy, trichlorine Ethyoxyl, trifluoro ethoxy.
" five yuan, hexa-atomic, seven yuan, the eight member heterocyclic ring containing nitrogen bases " of the present invention refer to substituted or unsubstituted at least one Ring, total annular atom number are five, six, seven, eight and containing the saturation of at least one nitrogen-atoms, fractional saturations and completely not The heterocyclic group of saturation.Preferably, described " five yuan, hexa-atomic, seven yuan, eight member heterocyclic ring containing nitrogen bases " are piperazinyl, pyridyl group, azepine Bicyclic alkyl, imidazole radicals, pyrazolyl, pyrrole radicals, triazolyl, pyridazinyl, pyrimidine radicals, pyrazinyl, piperidyl, triazine radical, or take Piperazinyl, pyridyl group, azabicycloalkyl, imidazole radicals, pyrazolyl, pyrrole radicals, triazolyl, pyridazinyl, pyrimidine radicals, the pyrazine in generation Base, piperidyl, triazine radical, wherein the substitution is selected from alkyl, hydroxyl, hydroxyalkyl, alkoxy, amino, alkyl monosubstituted amino, double alkane Base amino, acylamino-, alkyl amido, acrylamido, heteroarylamido, halogen, the alkyl of halogen substitution, halogen substitution Alkoxy, the preferably described substituent group be selected from C1-6Alkyl, hydroxyl, hydroxyl C1-6Alkyl, C1-6Alkoxy, amino, list C1-6Alkyl Amino, double C1-6Alkyl amino, acylamino-, C1-6Alkyl amido, acrylamido, heteroarylamido, halogen, halogen substitution C1-6The C that alkyl, halogen replace1-6Alkoxy.
" the 4-8 members naphthenic base " of the present invention refers to including the monocycle or two ring filling alkyl of 4-8 carbon atom, suitable ring Alkyl includes cyclobutyl, cyclopenta, cyclohexyl and suberyl etc..Other suitable naphthenic base include spiral shell amyl, two Huan [2.1.0] Amyl and two Huan [3.1.0]Hexyl etc..
The present invention " solvate " refer in a conventional sense solute (such as salt of reactive compound, reactive compound) and The compound that solvent (such as water) combination is formed.Solvent refers to the solvent of known to those of skill in the art or easy determination.Such as Fruit is water, then solvate is commonly referred to as hydrate, such as monohydrate, dihydrate, trihydrate etc..
" crystallization " of the present invention refers to the various solid forms that compound of the present invention is formed, including crystal form, nothing are calmly Shape.
" isomers " of the present invention includes compound along configuration structure body, rotamer and enantiomter.Configuration isomery Body refers to the cis-trans-isomer of cis or trans configuration.Rotamer refers to the stereoisomer generated due to singly-bound rotation.
" prodrug " of the present invention refers under the physiological condition of organism, due to being reacted and conversion cost with enzyme, hydrochloric acid in gastric juice etc. The compound of invention is converted to the compound of the present invention and/or by hydrochloric acid in gastric juice etc. by the oxidation of enzyme, reduction, hydrolysis etc. Hydrolysis etc. is converted to the compound of the present invention.
" the pharmaceutically acceptable salt " of the present invention refers to the pharmaceutically acceptable salt that the compound of the present invention is formed with acid, The acid includes but not limited to phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, maleic acid, malonic acid, mandelic acid, amber Acid, fumaric acid, acetic acid, lactic acid, nitric acid etc..
The present invention " pharmaceutical composition " refer to include any type compound as described herein, including isomers, prodrug, Solvate, the forms of protection of pharmaceutically acceptable salt or its chemistry and one or more pharmaceutically acceptable carriers it is mixed Close object.In claimed range, 3- ((1H- pyrrolo-es are refered in particular to;2,3-b]Pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- San Fujiajibenjis ]Benzamide hydrochloride salt or its isomers, solvate, The mixture of crystallization or prodrug and one or more pharmaceutically acceptable carriers.
The present invention " pharmaceutically acceptable carrier " refer to obvious irritation is not caused to organism and do not interfere to Give the bioactivity of compound and the carrier of property, including solvent, diluent or other excipient, dispersant, surfactant, Isotonic agent, thickener or emulsifier, preservative, solid binder, lubricant etc..Unless any conventional carrier medium and the present invention Compound is incompatible.It can include, but are not limited to carbohydrate as some examples of pharmaceutically acceptable carrier, such as lactose, Portugal Grape sugar and sucrose；Starch, such as cornstarch and potato starch；Cellulose and its derivates, such as sodium carboxymethylcellulose and Cellulose and cellulose acetate；Malt, gelatin etc..
" excipient " of the present invention, which refers to, to be added in Pharmaceutical composition with the further inert substance for promoting to give compound. Excipient may include calcium carbonate, calcium phosphate, various saccharides and a plurality of types of starch, cellulose derivative, gelatin, plant Oil, polyethylene glycol.
The present invention " prepare for treat and/or the drug of pre- preventing tumor in application " refer to that can inhibit tumour Growth, development and/or transfer, mainly to required human or animal to control give the compound of the present invention for the treatment of effective dose with Inhibit, slow down or reverse the growth, development or expanding of subject's tumour.
Specific implementation mode
Representative embodiment is protection model and is not intended to limit the present invention in order to better illustrate the present invention below It encloses.
1 3- acetenyl -4- methyl-N-&#91 of embodiment;4- ((4- methylpiperazine-1-yls) methyl) -3- San Fujiajibenjis ] The preparation of benzamide
The iodo- 4- methyl-N-&#91 of step 1 3-;4- (4- methylpiperazine-1-yls) methyl) -3- San Fujiajibenjis ]Benzamide Preparation
In the reactor be added 4- (4- methylpiperazine-1-yls methyl) -3- 5-trifluoromethylanilines (2.27g, 8.3mmol), The iodo- 4- methyl-benzoyl chlorides (10mmol) of 3-, 15ml tetrahydrofurans, 10ml triethylamines, are stirred at room temperature 4 hours.Saturation is added NaHCO3Solution washs, ethyl acetate and water extraction, saturation NaCl solution washing, anhydrous Na2SO4Dry, vacuum distillation removes molten Agent.Residue obtains title compound through silica gel column purification, is yellow oil.
1H NMR(500MHz,CDCl3)δ:8.39(s,1H,N-H),8.29(s,1H,Ar-H),7.88(d,1H,Ar-H), 7.86(s,1H,Ar-H),7.75(d,1H,Ar-H),7.73(d,1H,Ar-H),7.28(d,1H,Ar-H),3.62(s,2H, PhCH2),2.60(b,8H,4×-CH2),2.47(s,3H,-CH3),2.31(s,3H,-CH3)。
Step 2 3- Trimethylsilanylethynyl -4- methyl-N-[4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoros Jia Jibenji ]The preparation of benzamide
By step 1 gains (3.1g, 6.1mmol), Pd (PPh3)2Cl2(426mg, 0.61mmol), CuI (231mg, 1.21mmol) be placed in reactor, toluene 30ml is added and makees solvent, triethylamine 1ml maintains alkaline environment.Inert gas shielding Under, trimethylsilanylethyn (3.0g, 30.3mmol) is added into the mixture, 58 DEG C are stirred 24 hours.Reaction terminates, to Ethyl acetate is added in reaction mixture and water is extracted, merges organic layer, is washed, is added anhydrous with saturation NaCl solution Na2SO4It is dry.It is concentrated under reduced pressure, residue obtains title compound through silica gel column purification, is yellow solid.
1H NMR(500MHz,CDCl3)δ:8.30(s,1H,N-H),7.86(s,1H,Ar-H),7.83(d,1H,Ar-H), 7.72(s,1H,Ar-H),7.55(d,1H,Ar-H),7.41(d,1H,Ar-H),7.24(d,1H,Ar-H),3.60(s,2H, PhCH2),2.48(b,8H,4×-CH2),2.45(s,3H,-CH3),2.28(s,3H,-CH3),0.26(s,9H,3×-CH3)。
Step 3 3- acetenyl -4- methyl-N-[4- ((4- methylpiperazine-1-yls) methyl) -3- San Fujiajibenjis ]Benzene The preparation of formamide
Step 2 gains (1.59g, 3.3mmol), potassium carbonate (1.82g, 13.2mmol), 20ml methanol are mixed in instead It answers in device, under inert gas shielding, is stirred at room temperature 3 hours.Reaction terminates, and methanol is removed on Rotary Evaporators, and acetic acid second is added Ester and water are extracted, and organic layer is merged, and are washed with saturation NaCl solution, anhydrous Na is added2SO4It is dry.Then this is organic molten Liquid concentrates on a rotary evaporator, and residue obtains title compound through silica gel column purification, is yellow oily liquid.
1H NMR(500MHz,CDCl3)δ:10.47(s,1H,N-H),8.19(s,1H,Ar-H),8.08(s,1H,Ar-H), 8.04(d,1H,Ar-H),7.91(d,1H,Ar-H),7.70(d,1H,Ar-H),7.47(d,1H,Ar-H),4.50(s,1H, ≡ CH),3.56(s,2H,PhCH2),2.50(s,3H,-CH3),2.36(b,8H,4×CH2),2.15(s,3H,-CH3)。
2 3- of embodiment ((1H- Bi Kabings [2,3-b]Pyrazine -5- bases) acetenyl) -4- methyl-N-[4- ((4- methyl piperazines Piperazine -1- bases) methyl) -3- San Fujiajibenjis ]The preparation of benzamide
Compound (126mg, 0.3mmol), the bromo- 1H- Bi Kabings &#91 of 5- prepared by embodiment 1 is added in 10ml tube sealings;2, 3-b]Pyrazine (59mg, 0.3mmol), Pd (PPh3)2Cl2(63mg, 0.006mmol), CuI (18mg, 0.09mmol), 1mLEt3N And 5mLDMF, under inert gas shielding, 80 DEG C are stirred to react 8 hours.Reaction terminates, and is extracted with ethyl acetate and water, closes And organic layer, saturation NaCl solution washing, anhydrous Na2SO4It is dry.It is concentrated under reduced pressure, residue obtains described through silica gel column purification Compound is off-white powder.
1H NMR(500MHz,CDCl3)δ:8.91(br,1H,-NH),8.46(s,1H,Ar-H),8.02(d,1H,Ar-H), 7.98(s,1H,Ar-H),7.87(s,1H,Ar-H),7.85(s,-NH,1H),7.78-7.80(m,1H,Ar-H),7.69-7.70 (d,1H,Ar-H),7.60-7.62(m,1H,Ar-H),7.35(d,1H,Ar-H),6.72-6.73(m,1H,Ar-H),3.61(s, 2H,-CH2),2.60(s,3H,-CH3),2.54(b,8H,-CH2),2.33(s,3H,-CH3)。
ESI-MS m/z:[M+H]+=533.1, calculated value 533.2.
3 3- of embodiment ((1H- Bi Kabings [2,3-b]Pyrazine -5- bases) acetenyl) -4- methyl-N-[4- ((4- methyl piperazines Piperazine -1- bases) methyl) -3- San Fujiajibenjis ]Benzamide hydrochloride salt
Weigh 3- ((1H- Bi Kabings [2,3-b]Pyrazine -5- bases) acetenyl) -4- methyl-N-[4- ((4- methyl piperazines -1- Base) methyl) -3- San Fujiajibenjis ]Benzamide (30mg) is dissolved in 5mL methanol, and Hydrochloride/ethyl acetate is added dropwise extremely PH value is 3 or so, and 3h is stirred at room temperature, and decompression boils off volatile materials, and 50 DEG C of vacuum drying 5h obtain title compound.
1H NMR(300MHz,DMSO-d6)δ:12.34(s,1H),10.61(s,1H),10.25(b,1H),8.56(s, 1H),8.26(s,2H),8.14(d,1H),7.96-8.01(m,2H),7.73(d,1H),7.56(d,1H),6.67-6.69(m, 1H),3.70(s,2H),3.37(m,4H),2.89-3.06(m,4H),2.77(s,3H),2.61(s,3H)。
1H NMR(300MHz,DMSO-d6+D2O)δ:10.62(s,1H),8.57(s,1H),8.22(s,2H),8.07(d, 1H),7.93-7.99(m,2H),7.74(d,1H),7.56(d,1H),6.71(d,1H),3.70(s,2H),3.38-3.42(m, 2H),2.91-3.06(m,4H),2.81(s,3H),2.61(s,3H),2.42(m,2H)。
1 stability experiment of experimental example
It is placed 10 days under the conditions of illumination 4500Lx, the compound of the embodiment of the present invention 3 has very high stability, It the results are shown in Table 1.
Table 1
2 solubility experiment of experimental example
Different pH solution was configured under version Chinese Pharmacopoeia annex XV D buffer solution items according to 2010, is measured using HPLC methods Solubility.The compound of experiment display, embodiment 3 has extraordinary solubility, the results are shown in Table 2.
Table 2
pH 0.1M hydrochloric acid 2.0M hydrochloric acid
The compound of embodiment 3 193.2mg/ml 232.6mg/ml
3 bioavilability of experimental example is tested
1 experiment material
1.1 compound
Use the compound of above the embodiment of the present invention 3.Wherein, ORAL FORMULATION is physiological saline solution, is made 3mg/ml suspensions；Tail vein injection pharmaceutical formulation is volume ratio DMSO：Emulsifier EL-60：Physiological saline=1：30：69 Mixed solution, 2.5mg/ml solution is made.
1.2 animal
Male SD rat, every group each 3, weight 150g-250g, Shanghai western Poole-Bi Kai experimental animals Co., Ltd carries For.2~4 days environment laundering period are given before tested rat experiment, fasting 8-12h before being administered is administered water supply after 2h, is given after 4h Food.
1.3 reagent
Methanol (chromatographically pure)：Spectrum companies produce；
Acetonitrile (chromatographically pure)：Spectrum companies produce；
Remaining reagent is that commercially available analysis is pure.
1.4 instrument
The triple level four bars LC-MS instrument of 4000 types of American AB company API are furnished with electric spray ion source (ESI), LC- 20AD double pumps；SIL-20AC autosamplers；CTO-20AC column ovens；DGU-20A3R degassers；Analyst QS A01.01 Chromatographic work station；Milli-Q Superpure water machines (Millipore Inc)；Qilinbeier Vortex-5 oscillators；HITACHI Ⅹ II table-type high-speed refrigerated centrifuges of CF16R.
2 experimental methods
1) SD Rat Fasts but can free water after 12 hours, take 0 moment blank plasma；
2) rat 3 in step 1) is taken, gavage (Intragastricadministration, I.G.) give embodiment 3 compound 15mg/kg；
The rat 3 in step 1) is taken, tail vein (Intravenous administration, I.V.) give embodiment 3 compound 3mg/kg；
3) after gavage 10min, 30min, 1h, 2h, 4h, 6h, 8h, 10h, eyeground vein clump continuous blood sampling is in distribution for 24 hours Have in the EP pipes of heparin, upper plasma is taken after 8000rpm/min centrifugations 5min, -20 DEG C freeze, and wait for that LC-MS/MS is analyzed；
4) the blood concentration-time data obtained by step 3) are asked using WinNonlin softwares and calculate pharmacokinetics ginseng Number, is shown in Table 3.
5) 5min, 15min, 30min, 1h, 2h, 4h, 8h, 24 eyeground vein clump continuous blood samplings after tail vein injection administration In being distributed in the EP pipes of heparin, upper plasma is taken after 8000rpm/min centrifugations 5min, -20 DEG C freeze, and wait for LC-MS/MS points Analysis.
6) the blood concentration-time data obtained by step 5) are asked with WinNonlin softwares and calculate pharmacokinetics ginseng Number, is shown in Table 3.
3 pharmacokinetic parameter of table
(the Discovery of 3-&#91 such as Wei-Sheng Huang;2-(Imidazo[1,2-b]pyridazin-3-yl) ethynyl]-4-methyl-N-{4-[(4-methyl-piperazin-1-yl)-methyl]-3-(trifluoromethyl) phenyl}benzamide(AP24534),a Potent,Orally Active Pan-Inhibitorof Breakpoint Cluster Region-Abelson (BCR-ABL) Kinase Including the T315I Gatekeeper Mutant, J.Med.Chem.2010 (53) 4701-4719) report, it is oral to give Ponatinib15mg/kg, Cmax (Cmax) be 204.8ng/ml, oral administration biaavailability (F) are 18.2%.It can be seen that the C of the compound of the embodiment of the present invention 3maxIt is high In Ponatinib, there is higher oral administration biaavailability.
In addition, using a variety of cancer cell line, including the K562 leukaemia of K562 leukaemia cell, imatinib-resistant are thin Born of the same parents, Saos-2 OS-732 cells, Ovcar-3 Proliferation of Human Ovarian Cell, MDA-MB-231 human breast cancer cells and people source ABL T315I mutant enzymes carry out cell in vitro activity rating and ABL1 (T315I) junket to the compound of the embodiment of the present invention 3 Histidine kinase activity rating, the experimental results showed that, the compound of embodiment 3 is mutated to kinds of tumor cells, including T315I, is resistance to The leukaemia cell of medicine all has the inhibiting effect of highly significant.Therefore, 3- ((1H- Bi Kabings [2,3-b]Pyrazine -5- bases) second Alkynyl) -4- methyl-N-[4- ((4- methylpiperazine-1-yls) methyl) -3- San Fujiajibenjis ]Benzamide hydrochloride salt is wide spectrum BCR-ABL inhibitor, for treating the tumor patients in heilongjiang of drug resistance or resistance to tyrosine kinase inhibitor (TKI), such as slowly Property granulocytic leukemia (CML) chronic phase, rapid change period, the chronic grain of accelerated period patient and Philadelphia Chromosome Positive (Ph+) are thin The foreground that born of the same parents' leukaemia and Patients With Acute Lymphoblastic Leukemia have had.
Although being described in detail above to the present invention, however it is understood by skilled practitioners that without departing from this hair The present invention can be carry out various modifications and be changed under the premise of bright spirit and scope.The interest field of the present invention is not limited to It is described in detail made by above, and claims should be belonged to.

Claims (11)

1. a kind of pharmaceutical preparation, it includes 3- ((1H- Bi Kabings [2,3-b]Pyrazine -5- bases) acetenyl) -4- methyl-N-[4- ((4- methylpiperazine-1-yls) methyl) -3- San Fujiajibenjis ]Benzamide hydrochloride salt and one or more pharmaceutically may be used The carrier of receiving.
2. preparation according to claim 1, wherein the hydrochloride has the following structure：
3. according to the pharmaceutical preparation of claims 1 or 2, it is configured to be suitable for oral or parenteral.
4. according to the pharmaceutical preparation of claims 1 or 2, be tablet, pill, granule, pulvis, capsule, syrup, emulsion or Suspension.
5. a kind of pharmaceutical composition, it includes 3- ((1H- Bi Kabings [2,3-b]Pyrazine -5- bases) acetenyl) -4- methyl-N-[4- ((4- methylpiperazine-1-yls) methyl) -3- San Fujiajibenjis ]In benzamide hydrochloride salt, and the group selected from following composition It is one or more：Tyrosine protein enzyme inhibitor, EGFR inhibitor, VEGFR inhibitor, BCR-ABL inhibitor, c-kit suppressions Preparation, c-Met inhibitor, Raf inhibitor, mek inhibitor, inhibitors of histone deacetylase, VEGF antibody, EGF antibody, HIV kinases inhibitors and HMG-CoA reductase inhibitor.
6. pharmaceutical composition according to claim 5, wherein the hydrochloride has the following structure：
7. according to the pharmaceutical composition of claim 5 or 6, it is configured to be suitable for oral or parenteral.
8. it is tablet, pill, granule, pulvis, capsule, syrup, emulsion according to the pharmaceutical composition of claim 5 or 6 Or suspension.
9. any one of them pharmaceutical preparation of claim 1-4 or any one of them pharmaceutical composition of claim 5-8 Prepare for treat and/or the drug of pre- preventing tumor in application.
10. application according to claim 9, wherein the tumour is solid tumor or lymphatic cells tumour.
11. any one of them medicine of a kind of any one of them pharmaceutical preparation preparing claim 1-4 or claim 5-8 The method of compositions, including preparation 3- ((1H- Bi Kabings [2,3-b]Pyrazine -5- bases) acetenyl) -4- methyl-N-[4- ((4- methylpiperazine-1-yls) methyl) -3- San Fujiajibenjis ]The following steps of benzamide hydrochloride salt：
(1) preparation of the intermediate of formula 5：
A) intermediate of formula 3 is obtained by the reaction in the compound of the compound of formula 1 and formula 2；
B) intermediate of formula 4 is obtained by the reaction in the intermediate Yu trimethylsilyl acetylene of formula 3；
C) intermediate of formula 4 sloughs trimethylsilyl and obtains the intermediate of formula 5；
(2) preparation of the compound of Formulas I：
D) intermediate of formula 5 and the intermediate reaction of formula 6 obtain the compound of Formulas I；
Wherein, R1For hydrogen, R2For methyl, R3For 4- methylpiperazine-1-yls, R4For trifluoromethyl, W is-CH2, X C, Y C, M Selected from chlorine, bromine, iodine.
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