CN106890184B - Antitumor glutamine enzyme inhibitor and angiogenesis inhibitor pharmaceutical composition and its application - Google Patents
Antitumor glutamine enzyme inhibitor and angiogenesis inhibitor pharmaceutical composition and its application Download PDFInfo
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- CN106890184B CN106890184B CN201510961345.8A CN201510961345A CN106890184B CN 106890184 B CN106890184 B CN 106890184B CN 201510961345 A CN201510961345 A CN 201510961345A CN 106890184 B CN106890184 B CN 106890184B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
Abstract
The present invention relates to a kind of antitumor medicine composition and its applications.This kind of composition includes that glutamine enzyme inhibitor is used in combination with angiogenesis inhibitor.The present invention also specifically provides a kind of glutamine enzyme inhibitor such as formula (I) listed in specification, has significant inhibiting effect to glutaminase active.1/5th of dosage when the dosage of drug combination is only single use are up to 90% or more to the inhibition of tumor line growth, and significantly suppress the generation of these source of people tumour peripheral vessels and the transfer of tumour.Corresponding side effect is far below single drug.Therefore, a certain proportion of glutamine enzyme inhibitor and angiogenesis inhibitor drug combination have significant curative effect to oncotherapy, have significant collaboration and synergistic effect compared to single drug, are the antitumor combinations of a kind of high-efficiency low-toxicity.
Description
Technical field
The invention belongs to biomedicine technical fields, and in particular to treat malignant tumour by drug combination, in particular to
Malignant tumour is treated with glutamine enzyme inhibitor and angiogenesis inhibitor synergistic effect.
Background technique
Malignant tumour is to lead to one of human diseases and dead important persistent ailment, it is seriously endangered human health and life
Safety.In China, often hair property malignant tumour is based on lung cancer, gastric cancer, liver cancer, breast cancer.The traditional treatment of cancer has operation, puts
It treats, chemotherapy.In recent years, deepening continuously with Cytobiology and molecular biology research, researches and develops the drug for treating malignant tumour,
Especially screen high-efficiency low-toxicity, specifically for the drug of tumour cell signal specific access or target site more and more attention has been paid to,
It and is considered as the important directions of final radical cure malignant tumour.
The canceration of normal cell invariably accompany nucleic acid and protein synthesis dramatically increase.And the height of nucleic acid and protein
Speed synthesis is also the prerequisite of tumour cell rapid growth.The macromolecular synthesis process of these tumour cells requires constantly to mention
For required and nonessential amino acid.As the glutamine of amino acid the most abundant in human body, tumour cell growth and
Play the role of vital [referring to document: 1-3] in upsilonmorigenic process.And glutaminase is then that glutamine is newly old
One ring of key during metabolism.Glutaminase is located at the inner membrance of cell Mitochondria [referring to document: 4], can be catalyzed
The reaction of glutamic acid is generated by glutamine, glutamic acid is changed into α-ketoglutaric acid under the action of glutamte dehydrogenase, the bottom of with
The form of object enters tricarboxylic acid cycle, for tumour cell macromolecular synthesis provide metabolism intermediate [referring to document:
5].Scientific research proves that the high activity of glutaminase and the fast-growth of tumour cell are closely related [referring to document: 6].With
Antisense (antisense) mRNA of glutaminase go transfection ehrlich ascites cell, not only their growth be suppressed and
And form is also changed.The cancer cell transfected with antisense mRNA, is inoculated into Mice Body, such cancer cell loses completely
Production blastomogenic ability, and such mouse is also just the same with healthy animal [referring to document: 7].These scientific discoveries are filled
The active of clear glutaminase of defending oneself is closely related with tumour occurrence and development.Therefore, glutaminase has become antitumor
The target protein greatly paid close attention in therapy by people.In recent years, some small molecule glutamine enzyme inhibitor such as dithiadiazoles
Class compound BPTES (Bis-2- (5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide)
[referring to document: 8], heterocycle compound CB-839 (2- (pyridin-2-yl)-N- (5- (4- (6- (2- (3-
(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)but yl)-1,3,4-thiadiazol-2-
Yl) acetamide) it has been screened out, and clinical trial is entered in the U.S. as potential anti-tumor drug.But
It is that so far, in zoopery or clinical trial, these glutaminase micromolecular inhibitors are when being used alone to swollen
The inhibitory effect of tumor growth is very limited.
Except the canceration of normal cell, in malignant tumour generating process, meeting induction of vascular around it after cell carcinogenesis
It is formed (i.e. tumor angiogenesis, Tumor Angiongesis), this is the key that a ring in tumour growth.On the one hand, tumour
It needs by these new vessels itself to provide nutrient required for fast-growth, on the other hand, tumour cell can also pass through
These blood vessels enter circulation to shift diffusion.Therefore, one of the Key Strategy of antineoplaston is exactly to inhibit tumor vessel raw
At.Now, inhibiting the drug of Tumor Angiongesis has: bevacizumab (Bevacizumab, trade name: Avastin,
Avastin, Genentech/Roche)；Sorafenib (Sorafenib, trade name: Lei Shawa, Nexavar, Bayer)；Shu Ni
For Buddhist nun (Sunitinib, trade name: sotan, Sutent, Pfizer)；Po Malidu amine (Pomalidomide, trade name:
Pomalyst, Celgene) etc..Tumor Angiongesis is inhibited often to inhibit tumor vascular development by using targeted drug
Key factor in the process, such as vascular endothelial growth factor (Vascular endothelial growth factor,
VEGF) Lai Dacheng.Anti-VEGF antibody, such as bevacizumab (Bevacizumab, trade name: Avastin, Avastin,
Genentech/Roche) it is exactly first drug by FDA approval for the inhibition Tumor Angiongesis of clinical therapy of tumor.
However, bevacizumab (and drug of other targeting VEGF signals) has apparent side effect, themselves does not also press down directly
The growth of tumour cell processed.And clinically most patient can generate drug resistance [referring to document: 9-13].Therefore, tumour blood
This kind of drug of pipe formation inhibitor, such as bevacizumab, Sorafenib, Sutent etc. are expenses for considerable part patient
High and effect is simultaneously inapparent.
Summary of the invention
The present invention is joined by providing a kind of certain a effective amount of glutamine enzyme inhibitor and angiogenesis inhibitor
Medicine is shared, the fast-growth of tumour cell can be effectively inhibited, the transfer of angiogenesis and tumour around tumour, to oncotherapy
With significant curative effect, acquired antitumor action is substantially better than single drug, has significant collaboration and synergistic effect, is one
The antitumor combination of class high-efficiency low-toxicity.
The pharmaceutical composition of anti-malignant tumor provided by the present invention, which is characterized in that the glutamine enzyme inhibitor
As shown in logical formula (I) or its physiologically acceptable salt:
Wherein:
R0, R0' independently selected from pyridazinyl:
Or following general formula:
X is independently selected from S, O, C；Preferably S, C；More preferably S；Any hydrogen atom of CH unit can be replaced by alkyl.
Y is independently selected from N, O, S, C；Preferably N, O；More preferably N；Any hydrogen atom of NH or CH unit can be by alkyl
Replace.
R1, R2Independently selected from H or R3(CO):
R3Independently selected from H, OH, aryl, heteroaryl, heteroaryl alkyl, heteroaryloxy, (C1-C6) alkyl, O- (C1-
C6) alkyl, O- (C1-C6) alkyl-COOH, O- (C1-C6) alkyl-aryl-group, OCO- (C1-C6) alkyl, S- (C1-C6) alkyl-
Aryl, NO2 > NH2 > NH- (C1-C6) alkyl, N ((C1-C6) alkyl) 2, N- (C1-C6) alkyl-aryl-group；
Any of them free hydroxyl group can be acylated, with formation-C (O) R4；Preferably aryl, heteroaryl, S- (C1-C6)
Alkyl-aryl-group, N- (C1-C6) alkyl-aryl-group, O- (C1-C6) alkyl-aryl-group；More preferably aryl (phenyl), such as ethylbenzene；
R4 is independently selected from H or replaces alkyl, alkoxy, aminoalkyl, alkylaminoalkyl group, heterocyclylalkyl group, aralkyl or heterocycle
Alkoxy.
Term as used herein " aryl " refers to that wherein at least one ring is aromatic C6-12 monocycle hydrocarbon ring or dicyclic hydrocarbon
Ring.The example of the group includes phenyl, naphthalene and tetralyl.
Term as used herein " heteroaryl " refers to 5-6 member aromatic monocyclic or condensed 8-10 member aromatic bicyclic, described
Monocycle or bicyclic 1 to 4 hetero atom comprising being selected from oxygen, nitrogen and sulphur.The example of this kind of aromatic monocyclic includes thienyl, furans
Base, furan a word used for translation base (furazanyI), pyrrole radicals, triazolyl, tetrazole radical, imidazole radicals, oxazolyl, thiazolyl, oxadiazoles base, different thiophene
Oxazolyl, isoxazolyl, thiadiazolyl group, pyranose, pyrazolyl, pyrimidine radicals, pyridazinyl, pyrazinyl, pyridyl group, triazine radical, tetrazine
Base etc..The example of this kind of aromatic bicyclic include quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, pteridyl, cinnoline base,
Phthalazinyl (phthalazinyl), naphthalene cry base (naphthyridinyl), drawing diindyl base, different nitrogen, but base, azepine draw diindyl base
(azaindolyl), indolizine base (indolizinyl), indazolyl, purine radicals, pyrrolopyridinyl, furopyridyl, benzo
Furyl, isobenzofuran-base, benzothienyl, benzimidazolyl, benzoxazolyl, benzo isoxazolyl, benzothiazolyl,
Benzisothia oxazolyl, benzoxadiazole base, diazosulfide base and imidazopyridyl.
Term as used herein " (C1-C6) alkyl " refers to linear saturation hydrocarbyl group or branch containing 1 to 6 carbon atom
Saturation is through group.(C1-C6) example of alkyl group include methyl, it is ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, secondary
Butyl, tert-butyl, amyl, hexyl.Preferably, the hydrocarbyl group is straight chain.
In the presence of being with different enantiomter and/or diastereomeric form when the compounds of this invention (including it is double
The geometrical isomerism of key), the compound can be prepared as isomeric mixtures or racemic compound, but the present invention relates to all
This kind of enantiomter or isomer are whether deposited using optical voidness form or as the mixture with other isomers
?.Independent enantiomter or isomer can be obtained by methods known in the art, such as product or intermediate
Optical resolution (such as chiral chromatogram separation (for example, chirality HPLC)) or enantiomter synthetic method.Similarly, when this hair
When there is (for example, ketone/enol, amide/imidic acid) in the tautomeric forms that bright compound can be used as substitution, the present invention relates to
Isolated individual tautomeric body, and it is related to the tautomers mixture of all proportions.
The invention further relates to the officinal salt of above-mentioned general formula compound, the officinal salt is that those skilled in the art are known
, the acid salt of basic salt or inorganic base or organic base including inorganic acid and organic acid.The acid such as hydrochloric acid, hydrogen bromine
Acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, naphthalene sulfonic acids, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, lemon
Acid, lactic acid, oxalic acid, fumaric acid, succinic acid, maleic acid, benzoic acid etc..The alkali for example have alkali or alkaline earth metal sun from
Son or ammonium cation etc..
Described the compound of the present invention can be by general preparation method or other known methods [referring to document: 14]
It obtains.Preparing initial substance used in the compound and reagent can be bought or can be by this field skill from suppliers
The preparation of method known to art personnel.The generality route merely illustrates the side that the compounds of this invention can be synthesized by it
Method, and for those skilled in the art by reference to present disclosure, a variety of modifications of the route can be made
And it takes a hint.
The pharmaceutical composition of anti-malignant tumor provided by the present invention, which is characterized in that the glutamine enzyme inhibitor
It is BPTES (Bis-2- (5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide).
The pharmaceutical composition of anti-malignant tumor provided by the present invention, which is characterized in that the glutamine enzyme inhibitor
It is GB-002, as shown in formula (II):
2- phenyl-N- (6- ((1- (6- (2- (3- (trifluoromethoxy) phenyl) acetylamino) pyridazine -3- base) piperidines -4-
Base) amino) pyridazine -3- base) acetamide.
The pharmaceutical composition of anti-malignant tumor provided by the present invention, which is characterized in that the glutamine enzyme inhibitor
It is GB-016, as shown in formula (III):
2- phenyl-N- (5- ((1- (6- (2- (3- (trifluoromethoxy) phenyl) acetylamino) pyridazine -3- base) piperidines -4-
Base) amino) -1,3,4- thiadiazoles -2- base) acetamide.
The pharmaceutical composition of anti-malignant tumor provided by the present invention, which is characterized in that the glutamine enzyme inhibitor
It is GB-017, as shown in formula (IV):
2- phenyl-N- (5- ((1- (6- (2- (3- (trifluoromethoxy) phenyl) acetylamino) pyridazine -3- base) piperidines -4-
Base) oxygroup) -1,3,4- thiadiazoles -2- base) acetamide.
The pharmaceutical composition of anti-malignant tumor provided by the present invention, which is characterized in that the glutamine enzyme inhibitor
It is GB-042, as shown in formula (V):
2- phenyl-N- (5- (1- (5- (2- (3- (trifluoromethoxy) phenyl) acetylamino) -1,3,4- thiadiazoles -2- base)
Piperidin-4-yl amino) -1,3,4- thiadiazoles -2- base) acetamide.
The pharmaceutical composition of anti-malignant tumor provided by the present invention, which is characterized in that the glutamine enzyme inhibitor
It is GB-051, as shown in formula (VI):
2- (pyridin-4-yl)-N- (5- (1- (5- (2- (4- (trifluoromethoxy) phenyl) acetylamino) -1,3,4- thiophene two
Azoles -2- base) piperidin-4-yl amino) -1,3,4- thiadiazoles -2- base) acetamide.
The pharmaceutical composition of anti-malignant tumor provided by the present invention, which is characterized in that the glutamine enzyme inhibitor
It is GI-002, as shown in formula (VII):
N- (5- (1- (5- (2- (1H- pyrazol-1-yl) acetylamino) -1,3,4- thiadiazoles -2- base) piperidin-4-yl ammonia
Base) -1,3,4- thiadiazoles -2- base) -2- (1H- pyrazol-1-yl) acetamide.
The pharmaceutical composition of anti-malignant tumor provided by the present invention, which is characterized in that the glutamine enzyme inhibitor
It is GI-003, as shown in formula (VIII):
2- phenyl-N- (5- (4- ((5- (2- phenylacetamido) -1,3,4- thiadiazoles -2- base) amino) piperidines -1-
Base) -1,3,4- thiadiazoles -2- base) acetamide.
The pharmaceutical composition of anti-malignant tumor provided by the present invention, which is characterized in that the glutamine enzyme inhibitor
It is GI-005, as shown in formula (IX):
2- phenyl-N- (5- (4- ((5- (2- phenylacetamido) -1,3,4- thiadiazoles -2- base) oxygroup) piperidines -1-
Base) -1,3,4- thiadiazoles -2- base) acetamide.
The pharmaceutical composition of anti-malignant tumor provided by the present invention, which is characterized in that the glutamine enzyme inhibitor
It is GI-006, as shown in formula (X):
N2Phenethyl-N5(1- (5- (phenyl ethylamine) -1,3,4- thiadiazoles -2- base) piperidin-4-yl) -1,3,4- thiadiazoles -
2,5- diamines.
The pharmaceutical composition of anti-malignant tumor provided by the present invention, which is characterized in that the glutamine enzyme inhibitor
It is GI-024, as shown in formula (XI):
2- (4- aminophenyl)-N- (5- (4- (5- (2- phenylacetamido) -1,3,4- thiadiazoles -2- base amino) piperazine
Pyridine -1- base) -1,3,4- thiadiazoles -2- base) acetamide.
The pharmaceutical composition of anti-malignant tumor provided by the present invention, which is characterized in that the glutamine enzyme inhibitor
It is GI-036, as shown in formula (XII):
2- (2- chlorine pyrimidine -5- base)-N- (5- (1- (5- (2- (4- (trifluoromethoxy) phenyl) acetylamino) -1,3,4-
Thiadiazoles -2- base) piperidin-4-yl amino) -1,3,4- thiadiazoles -2- base) acetamide.
The pharmaceutical composition of anti-malignant tumor provided by the present invention, which is characterized in that the Tumor Angiongesis inhibits
Agent is bevacizumab (Bevacizumab, trade name: Avastin, Avastin, Genentech/Roche)；Or Sorafenib
(Sorafenib, trade name: Lei Shawa, Nexavar, Bayer)；Or Sutent (Sunitinib, trade name: sotan,
Sutent, Pfizer)；Or Po Malidu amine (Pomalidomide, trade name: Pomalyst, Celgene).
The pharmaceutical composition of anti-malignant tumor provided by the present invention, which is characterized in that the glutamine enzyme inhibitor
It is BPTES (Bis-2- (5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide), it is described swollen
Tumor angiogenesis inhibitors are bevacizumab (Bevacizumab, trade names: Avastin, Avastin, Genentech/
Roche)；Or Sorafenib (Sorafenib, trade name: Lei Shawa, Nexavar, Bayer)；Or Sutent
(Sunitinib, trade name: sotan, Sutent, Pfizer)；Or Po Malidu amine (Pomalidomide, trade name:
Pomalyst, Celgene).
The pharmaceutical composition of anti-malignant tumor provided by the present invention, which is characterized in that the glutamine enzyme inhibitor
GB-016, the angiogenesis inhibitor be Po Malidu amine (Pomalidomide, trade name: Pomalyst,
Celgene)；Or Sorafenib (Sorafenib, trade name: Lei Shawa, Nexavar, Bayer)；Or Sutent
(Sunitinib, trade name: sotan, Sutent, Pfizer)；Or bevacizumab (Bevacizumab, trade name: Avastin,
Avastin, Genentech/Roche).
The pharmaceutical composition of anti-malignant tumor provided by the present invention, which is characterized in that the glutamine enzyme inhibitor
GI-003, the angiogenesis inhibitor be bevacizumab (Bevacizumab, trade name: Avastin,
Avastin, Genentech/Roche)；Or Sorafenib (Sorafenib, trade name: Lei Shawa, Nexavar, Bayer)；Or
Sutent (Sunitinib, trade name: sotan, Sutent, Pfizer)；Or Po Malidu amine (Pomalidomide, commodity
Name: Pomalyst, Celgene).
The pharmaceutical composition of anti-malignant tumor provided by the present invention, which is characterized in that the glutamine enzyme inhibitor
GI-005, the angiogenesis inhibitor be Po Malidu amine (Pomalidomide, trade name: Pomalyst,
Celgene)；Or Sorafenib (Sorafenib, trade name: Lei Shawa, Nexavar, Bayer)；Or Sutent
(Sunitinib, trade name: sotan, Sutent, Pfizer)；Or bevacizumab (Bevacizumab, trade name: Avastin,
Avastin, Genentech/Roche).
The pharmaceutical composition of anti-malignant tumor provided by the present invention, which is characterized in that the glutamine enzyme inhibitor
GI-006, the angiogenesis inhibitor be Sorafenib (Sorafenib, trade name: Lei Shawa, Nexavar,
Bayer)；Or Sutent (Sunitinib, trade name: sotan, Sutent, Pfizer)；Or Po Malidu amine
(Pomalidomide, trade name: Pomalyst, Celgene)；Or bevacizumab (Bevacizumab, trade name: A Wasi
Fourth, Avastin, Genentech/Roche).
It is a further object to provide the pharmaceutical compositions in the drug of preparation treatment tumor disease
Using.
The pharmaceutical preparation of anti-malignant tumor provided by the present invention is made with the pharmaceutical composition of above-mentioned anti-malignant tumor
For active constituent, and it is aided with acceptable pharmaceutic adjuvant, carrier and/or excipient, various preparations are made, e.g., but is not limited to,
Oral solution, capsule and pill, oral administration mixed suspension, solid dispersions, capsule, sustained release agent, granule, tablet, injection, ointment, patch, plant
Enter agent etc..
Pharmaceutical acceptable carrier, auxiliary agent and medium in Pharmaceutical composition for use in the present invention are normal in pharmaceutical formulating art
Rule those of use, including but not limited to, sugar, sugar alcohol, starch, ion-exchanger, aluminium oxide, aluminum stearate, lecithin, serum
Albumen (such as human serum albumins), buffer substance (such as phosphate), glycerol, sorbic acid, potassium sorbate, saturation plant fat
Partial glyceride mixtures, water, salt or electrolyte (such as protamine sulfate), disodium hydrogen phosphate, the potassium hydrogen phosphate, chlorination of acid
Sodium, zinc salt, cabosil, magnesium trisilicate, polyvinylpyrrolidone, the substance based on cellulose, polyethylene glycol, carboxymethyl are fine
Tie up plain sodium, polyacrylate, wax, polyethylene-polypropylene oxide-block polymer, polyethylene glycol and lanolin.
The constituent of combination preparation of the invention can simultaneously, separately or order of administration.
Combination preparation of the invention can be used for for include the mankind mammal in find include lung, leukaemia,
The institute of melanoma, liver, mammary gland, ovary, prostate, stomach, pancreas, kidney, colon and central nerve neuroma or cancer
Have in the treatment of type.Preferably, for non-small cell lung cancer, the treatment of breast cancer, glioma, liver cancer.
Pharmaceutical composition of the invention may also contain one or more other active medicine components.Drug of the invention
Combination can be with one or more one piece of active medicine component other administrations.The composition can be containing pharmaceutical composition of the present invention
With the form of the single composition of one or more other active medicine components.Alternatively, the composition can be two or more
The form of individual combination of compositions, wherein pharmaceutical composition of the invention is included in a kind of composition, it is one or more in addition
Active medicine component be included in one or more individual compositions in.It is described other in the pharmaceutical composition
Active medicine component for example can be another anti-tumor drug.
Chemical structural formula provided by the present invention glutamine enzyme inhibitor shown in formula I is treated or prevented in preparation
Increase the purposes in the drug in relation to illness with glutaminase active.Wherein, glutamine enzyme inhibitor is GB-002, GB-
016、GB-017、GB-042、GB-051、GI-002、GI-003、GI-005、GI-006、GI-024、GI-036。
Term used herein " certain a effective amount of ", refers to each component in the pharmaceutical composition of anti-malignant tumor
Amount, the amount are enough to realize the fast-growth of required inhibition tumour cell, the transfer of angiogenesis and tumour around tumour
Effect, belong to the invention scope.Present invention research also indicates that different tumor cell types to the sensitive journey of the composition
Degree is distinguishing.
The present invention will seriously combine and exempt from using multiple will be implanted into from the tumor tissues of patient in specific zoopery
The source of people tumour strain that epidemic disease deficient mice (Severe combined immunodeficiency mice, SCID mice) is established
Mouse model (patient-derived xenograft mice model, PDX model), glutamine enzyme inhibitor and swollen
The one third of the drug combination of tumor angiogenesis inhibitors dosage when dosage is only two kinds of inhibitor single uses is to five points
One of in the case where, to these tumor lines growth inhibition be up to 90% or more.And to these when two kinds of inhibitor single uses
The inhibition only about 5%-20% of tumor line growth.Immunohistochemical experiment also indicates that above-mentioned drug combination significantly inhibits
The generation of these source of people tumour peripheral vessels and tumour are shifted to lung.In contrast, under similarity condition, two kinds of inhibitor
It does not make significant difference to the generation of tumour peripheral vessels and tumour to lung's transfer when single use.In similar zoopery
In, to hepatic carcinoma strain, glioma tumor line, the research of breast cancer tumour strain has obtained similar result.
Based on above series of studies as a result, and in view of five points of dosage when the dosage of drug combination is only single use
One of, corresponding side effect is far below single drug.Therefore, a certain proportion of glutamine enzyme inhibitor and Tumor Angiongesis suppression
Agents medication has significant curative effect to oncotherapy, has significant collaboration and synergistic effect compared to single drug, is one
The antitumor combination of class high-efficiency low-toxicity.The relevant molecular biology research of the present invention also illustrates this kind of pharmaceutical composition tools
There is the molecule mechanism of significant synergistic function.
Detailed description of the invention
Fig. 1 is that BPTES and GI-003 inhibits recombination glutaminase active；
Fig. 2 is that BPTES and GI-003 inhibits tumour cell MDA-MB231 glutamine enzymatic activity；
Fig. 3 is the growth that GI-003 inhibits tumour cell；
Fig. 3 A shows GI-003 to the growth inhibition of non-small-sized lung carcinoma cell CRL-5803 (ATCC)；
Fig. 3 B shows GI-003 to the growth inhibition of breast cancer cell MDA-MB231；
Fig. 3 C shows GI-003 to the growth inhibition of human glioma cell U87 (ATCC)；
Fig. 4 is the influence that GI-003 grows normal mammary epithelial HMEC；
Fig. 5 is the inhibition of glutamine enzyme inhibitor and angiogenesis inhibitor pharmaceutical composition to mouse interior tumor
Effect；
Fig. 5 A shows that bevacizumab and BPTES pharmaceutical composition generate breast carcinoma cell strain MDA-MB231 in Mice Body
The inhibiting effect of the growth of tumour；
Fig. 5 B shows that Po Malidu amine and GI-005 pharmaceutical composition are raw to breast carcinoma cell strain MDA-MB231 in Mice Body
At the inhibiting effect of the growth of tumour；
Fig. 5 C shows that Sorafenib and GI-006 pharmaceutical composition generate breast carcinoma cell strain MDA-MB231 in Mice Body
The inhibiting effect of the growth of tumour；
Fig. 5 D shows that GI-003 and bevacizumab pharmaceutical composition generate tumour to human lung carcinoma cell line A549 in Mice Body
Growth inhibiting effect；
Fig. 5 E shows that GI-003 and bevacizumab pharmaceutical composition generate tumour to human lung carcinoma cell line A549 in Mice Body
Tumor Angiongesis inhibiting effect；
Fig. 6 is the source of people of glutamine enzyme inhibitor and angiogenesis inhibitor pharmaceutical composition to mouse et al. Ke
The inhibiting effect for the tumour strain (PDX model) that tumor tissues are established；
Fig. 6 A shows GI-003 and bevacizumab pharmaceutical composition to the source of people lung cancer tumor strain of mouse et al. Ke
HLC-3 (Human lung cancer-3) generates the inhibiting effect of the growth of tumour；
Fig. 6 B shows BPTES and bevacizumab pharmaceutical composition to the breast cancer tumour strain HBC-2 of mouse et al. Ke
(Human breast cancer-2) generates the inhibiting effect of the growth of tumour；
Fig. 6 C shows GI-003 and bevacizumab pharmaceutical composition to the source of people lung cancer tumor strain of mouse et al. Ke
The inhibiting effect of the Tumor Angiongesis of HLC-3；
Fig. 6 D shows BPTES and bevacizumab pharmaceutical composition to the breast cancer tumour strain HBC-2 of mouse et al. Ke
Tumor Angiongesis inhibiting effect.
Specific embodiment
By following detailed description combination attached drawing it will be further appreciated that the features and advantages of the invention.Provided implementation
Example is only the explanation to the method for the present invention, remaining content without limiting the invention in any way announcement.In the following example
Test method without specific conditions, usually according to conventional conditions or according to the manufacturer's recommendations.
Unless otherwise indicated, the meaning of whole technical term and scientific words used in this specification with institute of the present invention
It is identical to belong to the meaning that those skilled in the art are commonly understood by.But if any conflict, it is subject to this specification comprising definition.
The system of [embodiment 1] glutamine inhibitor compound GI-003 (glutaminase inhibitor-003)
It is standby
Present embodiments provide the preparation method of glutamine enzyme inhibitor GI-003, specific steps are as follows:
(1) by equimolar thiosemicarbazides and ethoxyacetic acid under the catalysis of phosphorous oxychloride, 90 DEG C of reflux 3 are small
When.Reaction mixture is cooled to room temperature, water on the rocks, with sodium hydroxide tune pH=14.White precipitate is washed with water.Vacuum is dry
It is dry.As intermediate product [1]
5-(ethoxymethyl)-1,3,4-thiadiazol-2-amine
(5- (ethoxyl methyl) -1,3,4- thiadiazoles -2- amine)
(2) intermediate product [1] is mixed with equimolar phenyllacetyl chloride and pyridine, it is uniform to be heated to mixture, solution
It is cooled to room temperature, is filtered after methanol is added, leave thick solid, as intermediate product [2]
N-(5-(hydroxymethyl)-1,3,4-thiadiazol-2-yl)-2-phenylacetamide
(N- (5- (ethoxyl methyl) -1,3,4- thiadiazoles -2- base) -2- phenyl acetamide)
(3) by intermediate product [2] under sulfuric acid medium, crack ether chain with hydrogen bromide (or hydrogen iodide), generation alcohol, then plus
Enter potassium bichromate and sulfuric acid, is allowed to the generation further aoxidized acid, adds acetic acid (80 DEG C -90 DEG C) reflux oxidation and slough heterocycle
On C, filtered with methanol extraction, as intermediate product [3]
N-(5-hydroxy-1,3,4-thiadiazol-2-yl)-2-phenylacetamide
(N- (5- hydroxyl -1,3,4- thiadiazoles -2- base) -2- phenyl acetamide)
(4) by intermediate product [3] be added be equivalent to intermediate product [3] gram-molecular weight half to amino piperidine.In sulphur
Reflux 1-2 hours is reheated under acid medium.Reaction product adds methanol extraction to filter.Thick solid is recrystallized with dimethyl sulfoxide, as
Final product GI-003 (VIII).
2-phenyl-N-(5-(4-((5-(2-phenylacetamido)-1,3,4-thiadiazol-2-yl)amino)
piperidin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide
2- phenyl-N- (5- (4- ((5- (2- phenylacetamido) -1,3,4- thiadiazoles -2- base) amino) piperidines -1-
Base) -1,3,4- thiadiazoles -2- base) acetamide
[embodiment 2]: the system of glutamine inhibitor compound GI-006 (glutaminase inhibitor-006)
It is standby
Present embodiments provide the preparation method of glutamine enzyme inhibitor GI-006, specific steps are as follows:
(1) by equimolar thiosemicarbazides and ethoxyacetic acid under the catalysis of phosphorous oxychloride, 90 DEG C of reflux 3 are small
When.Reaction mixture is cooled to room temperature, water on the rocks, with sodium hydroxide tune pH=14.White precipitate is washed with water.Vacuum is dry
It is dry.As intermediate product [1]
5-(ethoxymethyl)-1,3,4-thiadiazol-2-amine
(5- (ethoxyl methyl) -1,3,4- thiadiazoles -2- amine)
(2) intermediate product [1] is mixed with equimolar phenyllacetyl chloride and pyridine, it is uniform to be heated to mixture, solution
It is cooled to room temperature, is filtered after methanol is added, leave thick solid, as intermediate product [2]
N-(5-(hydroxymethyl)-1,3,4-thiadiazol-2-yl)-2-phenylacetamide
(N- (5- (ethoxyl methyl) -1,3,4- thiadiazoles -2- base) -2- phenyl acetamide)
(3) by intermediate product [2] under sulfuric acid medium, crack ether chain with hydrogen bromide (or hydrogen iodide), generation alcohol, then plus
Enter potassium bichromate and sulfuric acid, is allowed to the generation further aoxidized acid, adds acetic acid (80 DEG C -90 DEG C) reflux oxidation and slough heterocycle
On C, filtered with methanol extraction, as intermediate product [3]
N-(5-hydroxy-1,3,4-thiadiazol-2-yl)-2-phenylacetamide
(N- (5- hydroxyl -1,3,4- thiadiazoles -2- base) -2- phenyl acetamide)
(4) by intermediate product [3] and suitable sodium hydroxide solution, hydrazine and diethylene glycol ether heat together, become hydrazine
Hydrazone.Then water and extra hydrazine are steamed, when temperature reaches hydrazone and starts temperature (195 DEG C -200 DEG C) decomposed, then flows back, make
N2 is released.Under normal pressure, reaction is 3-5 hours.Product can be filtered with methanol extraction to get intermediate product [4]
5-(phenethylamino)-1,3,4-thiadiazol-2-ol
(5- (PhenethyIamino) -1,3,4- thiadiazoles -2- alcohol)
(5) by intermediate product [4] be added be equivalent to intermediate product [4] gram-molecular weight half to amino piperidine.In sulphur
Reflux 1-2 hours is reheated under acid medium.Reaction product adds methanol extraction to filter.Thick solid is recrystallized with dimethyl sulfoxide, as
Final product GI-006 (X).
N2-phenethyl-N5-(1-(5-(phenethylamino)-1,3,4-thiadiazol-2-yl)
piperidin-4-yl)-1,3,4-thiadi azole-2,5-diamine
(N2Phenethyl-N5(1- (5- (phenyl ethylamine) -1,3,4- thiadiazoles -2- base) piperidin-4-yl) -1,3,4- thiophene two
Azoles -2,5- diamines)
Inhibition of [embodiment 3] the compound GI-003 to recombination glutaminase active
In expression in escherichia coli and the recombinant protein of mouse glutaminase (molecular weight 66kD) is prepared, with different dense
Its enzymatic activity is surveyed after compound GI-003 or the BPTES processing of degree.Specific step is as follows: having the end N- to be connected with a group ammonia using clone
The pET28a plasmid (Novagen: catalog number (Cat.No.): 69864-3) of the gene of the mouse glutaminase of acid is in expression in escherichia coli
Mouse glutaminase.The recombination glutamine zymoprotein is further purified with anion exchange chromatography.By 1 μM of glutamy
Compound of the amine enzyme recombinant protein in the buffer of 57 μM of Tris- acetic acid (pH8.6) and 0.25 μM of EDTA with various concentration
GI-003 or known glutamine enzyme inhibitor BPTES-as control plays warm bath, and final volume is 80 μ l, rotates 30 points
Clock.Compound GI-003 or BPTES are diluted with DMSO, and the volume being added is made to keep constant (5 μ l) in different reactions.So
Glutamine is added afterwards makes 115 μ l of final volume, and final concentration of 17 μM, reaction carries out 1 hour at 37 DEG C, and 10 μ l are then added
3M hydrogen chloride terminates reaction.It is added in second reaction from 10 μ l are taken out in first reaction, second reaction contains 114
μM Tris-HCl (pH 9.4), 0.35 μM of ADP, the glutamte dehydrogenase of 1.7 μM of NAD and 6.3U/ml, final volume are 228 μ
l.Second reaction carries out 45 minutes at room temperature, measures its absorption value, under the wavelength of 340nm then to calculate glutamine
The activity of enzyme.The results show that compound GI-003 has significant inhibiting effect to glutaminase active, and it inhibits to make
With being much better than known glutamine enzyme inhibitor BPTES: its IC50About 50nM is far below BPTES (Fig. 1).
Inhibition of [embodiment 4] the compound GI-003 to tumour cell glutamine enzymatic activity
The separate mitochondria from the breast cancer cell MDA-MB231 or neuroglial cytoma U87 of identical quantity, tumour are thin
Born of the same parents are handled through the compound GI-003 or BPTES of various concentration, do paddy to the mitochondria separated in the cell under different situations
The active measurement of transglutaminase.The measurement result of MDA-MB231 cell glutamine enzymatic activity is shown in Fig. 2.As a result
It has been shown that, compound GI-003 has significant inhibiting effect to glutaminase active, and its inhibiting effect is much better than oneself and knows
Glutamine enzyme inhibitor BPTES (Fig. 2).
Inhibiting effect of [embodiment 5] the compound GI-003 to growth of tumour cell
By non-small-sized lung carcinoma cell CRL-5803, breast cancer cell MDA-MB231 or neuroglial cytoma U87 culture exist
In the culture solution of RPMI 1640, be added 10% fetal calf serum, at the same with compound GI-003 (concentration 250nM) or
DMSO handles cell, and cell count was carried out at 1,2,4,6 day (cell growth is quantitative).As a result as shown in Fig. 3 A, 3B and 3C,
Compound GI-003 of the present invention can inhibit CRL-5803, the growth of MDA-MB231 or U87 cell.
Influence of [embodiment 6] the compound GI-003 to normal cell
By mankind's normal mammary epithelial HMEC culture in MEGM (Lonza) complete culture solution, with 250n Μ chemical combination
Object GI-003 or DMSO processing, respectively progress cell count in 1,2,4,6,8 day (cell growth is quantitative).The results show that changing
Growth of the object GI-003 for normal HMECs is closed without significantly influencing (Fig. 4).
Inhibiting effect of [embodiment 7] pharmaceutical composition of the present invention to mouse interior tumor
7.1, BPTES/ bevacizumab generates the inhibiting effect of tumour to breast carcinoma cell strain in Mice Body
By breast cancer cell MDA-MB231 (3 × 106) it is subcutaneously injected into Reconstruction in Sever Combined Immunodeciency Mice (SCID
Mice, National Cancer Institute) flank, tumour grows to about 200mm after 18 days3, start to use glutaminase
Processing tumour is used in combination in inhibitor BPTES or angiogenesis inhibitor bevacizumab or the two, and method is: every
The glutamine enzyme inhibitor BPTES (2mg/kg mouse weight) of 200 μ l is injected intraperitoneally every two days, (2mg/kg is small for bevacizumab
Mouse weight) or the two joint, persistently handle 10 days.Control-animal injects the same hydrotropy of not drug containing with same method
Carrier.During this period, every 2-3 days measurement tumor sizes calculate the volume [long (mm) × wide (mm) × height (mm)/2] of tumour.Knot
Fruit shows (Fig. 5 A), after 10 days, compared with the control group, when glutamine enzyme inhibitor or bevacizumab are used alone, to tumour
The inhibition of growth respectively may be about 5% and 16%, and be up to 90% to the inhibition of tumour growth when the two combination.Illustrate the medicine group
Closing when object is injected intraperitoneally into mouse has significant addition effect, reaches tumour and plays positive therapeutic effect to tumour.
7.2, GI-005/ Po Malidu amine generates the inhibiting effect of tumour to breast carcinoma cell strain in Mice Body
By breast cancer cell MDA-MB231 (3 × 106) it is subcutaneously injected into Reconstruction in Sever Combined Immunodeciency Mice (SCIDmice)
Flank, tumour grows to about 200mm after 18 days3, start to be inhibited with glutamine enzyme inhibitor GI-005 or Tumor Angiongesis
Processing tumour is used in combination in agent Po Malidu amine (Pomalidomide) or the two, and method is: being every other day injected intraperitoneally
200 μ l GI-005 (2mg/kg mouse weight), Po Malidu amine (0.5mg/kg mouse weight) or the two joint, it is lasting to locate
Reason 10 days.Control-animal injects the same hydrotropy carrier of not drug containing with same method.During this period, measurement in every 2-3 days is swollen
Tumor size calculates the volume of tumour.(Fig. 5 B) as the result is shown, after 10 days, compared with the control group, glutamine enzyme inhibitor or amber
When Ma Lidu amine is used alone, 2% and 40% respectively may be about to the inhibition of tumour growth, and to tumour growth when the two combination
Inhibit up to 80%.
7.3, GI-006/ Sorafenib generates the inhibiting effect of tumour to breast carcinoma cell strain in Mice Body
By breast cancer cell MDA-MB231 (3 × 106) it is subcutaneously injected into Reconstruction in Sever Combined Immunodeciency Mice (SCID
Mice flank), tumour grows to about 200mm after 18 days3, start with glutamine enzyme inhibitor GI-006 or Tumor Angiongesis
Processing tumour is used in combination in inhibitor Sorafenib (Sorafenib) or the two, and method is: being every other day injected intraperitoneally
The glutamine enzyme inhibitor GI-006 (2mg/kg mouse weight) of 200 μ l, Sorafenib (20mg/kg mouse weight), or
The two joint, is persistently handled 10 days.Control-animal injects the same hydrotropy carrier of not drug containing with same method.In this phase
Between, every 2-3 days measurement tumor sizes calculate the volume of tumour.(Fig. 5 C) as the result is shown, after 10 days, compared with the control group, paddy ammonia
When lactamase inhibitor or Sorafenib are used alone, 7% and 25% respectively may be about to the inhibition of tumour growth, and the two is combined
When to the inhibition of tumour growth up to 70%.
7.4, GI-003/ bevacizumab generates the inhibiting effect of tumour to lung cancer cell line in Mice Body
By lung cell A549 (3 × 106) it is subcutaneously injected into the side of body of Reconstruction in Sever Combined Immunodeciency Mice (SCID mice)
Abdomen, tumour grows to about 200mm after 24 days3, start with glutamine enzyme inhibitor GI-003 or angiogenesis inhibitor shellfish
It cuts down monoclonal antibody or processing tumour is used in combination in the two, method is: the GI-003 (0.5mg/ of 200 μ l is every other day injected intraperitoneally
Kg mouse weight), bevacizumab (2mg/kg mouse weight) or the two joint are persistently handled 12 days.Control-animal is with equally
Method injection not drug containing same hydrotropy carrier.During this period, every 2-3 days measurement tumor sizes, calculate the volume of tumour
[long (mm) × wide (mm) × height (mm)/2].(Fig. 5 D) as the result is shown, compared with the control group, glutamine enzyme inhibitor GI-003
Or when bevacizumab exclusive use, 5% and 15% respectively may be about to the inhibition of tumour growth, and to tumour growth when the two combination
Inhibition be up to 85%.The tumour generated in experiment and perienchyma are taken out, carry out immunohistochemical study after slice.Using anti-
CD31 antibodies on tumor peripheral vessels carry out immune labeled and observe under immunofluorescence microscopy and count quantitative.As the result is shown
(Fig. 5 E), compared with the control group, when glutamine enzyme inhibitor GI-003 or bevacizumab are used alone, to Tumor Angiongesis
Without obvious inhibiting effect (< 5%), and 70% or more is up to the inhibition of Tumor Angiongesis when the two combination.Illustrate the medicine
Compositions have significant addition effect when being injected intraperitoneally into mouse, positive therapeutic effect is played to tumour.
7.5, to the inhibiting effect of the source of people tumour growth of mouse et al. Ke
The tumor tissues about 8mm of breast cancer patients will be derived from3Fritter be implanted into Reconstruction in Sever Combined Immunodeciency Mice (SCID
Mice mammary gland), or the tumor tissues about 8mm that lung cancer patient will be derived from3Fritter be implanted into Reconstruction in Sever Combined Immunodeciency Mice
(SCID mice's) is subcutaneous, establishes corresponding source of people tumor mouse model (PDX model), after 2-6 weeks, tumour is grown to about
120mm3, start that place is used in combination with glutamine enzyme inhibitor or angiogenesis inhibitor bevacizumab or the two
Manage tumour, method is: be injected intraperitoneally every three days 200 μ l glutamine enzyme inhibitor (BPTES:2mg/kg mouse weight,
GI-003:0.5mg/kg mouse weight), bevacizumab (2mg/kg mouse weight) or the two joint persistently handle 4-6
Week.Control-animal injects the same hydrotropy carrier of not drug containing with same method.During this period, tumor size is measured weekly,
Calculate the volume of tumour.Source of people lung cancer tumor strain HLC-3 (Fig. 6 A) and source of people breast cancer tumour strain HBC-2 (figure is shown in Fig. 6
6B) as a result, selected glutamine enzyme inhibitor is respectively compound GI-003 and BPTES.Compared with the control group, glutamy
When amine enzyme inhibitor or bevacizumab are used alone, 15% is below to the inhibition of tumour growth, and to tumour when the two combination
The inhibition of growth is up to 90% or more.It is similar with being tested in 7.4, after the drug-treated phase, tumour and perienchyma are taken out,
Immunohistochemical study is carried out after slice.It carries out immune labeled using 1 antibodies on tumor peripheral vessels of AntiCD3 McAb and is shown in immunofluorescence
Micro- microscopic observation simultaneously counts quantitative.(Fig. 6 C and 6D) as the result is shown, compared with the control group, glutamine enzyme inhibitor GI-003/
When BPTES or bevacizumab are used alone, to Tumor Angiongesis without obvious inhibiting effect (respectively less than 12%), and the two is combined
When 75% or more is up to the inhibition of Tumor Angiongesis.The pharmaceutical composition is injected intraperitoneally into mouse Shi Youxian the above description shows that
Write addition effect.Positive therapeutic effect is played to tumour.
The inhibiting effect that [embodiment 8] pharmaceutical composition of the present invention shifts mouse interior tumor
Using source of people tumor mouse model (PDX model) described in 7.5 is similar to, after about 6 weeks, tumour is grown to about
100mm3, start that (shellfish is cut down with glutamine enzyme inhibitor (GI-003, BPTES or CB-839) or angiogenesis inhibitor
Monoclonal antibody (Bevacizumab) or Sutent (Sunitinib, 20mg/kg mouse weight)) or the two that processing is used in combination is swollen
Tumor, processing method are identical as described in 7.5.After persistently handling 4-6 weeks, mouse lung is taken out, is sliced, a group change research is carried out,
Source of people tumour is observed in the transfer of mouse lung.Transfer of the source of people breast cancer tumour strain HBC-5 of height transfer in mouse lung
It the results are shown in Table 1-3.By Tables 1 and 2 as it can be seen that compared with the control group, glutamine enzyme inhibitor (GI-003 or BPTES) or shellfish are cut down
When monoclonal antibody is used alone, to tumour mouse lung transfer without obvious inhibiting effect, and the two when being combined to tumour in mouse
The inhibition of the transfer of lung is up to 85% or more.And glutaminase inhibitor C B-839 and the easypro Buddhist nun of angiogenesis inhibitor
Also there is similar effect (table 3) for the pharmaceutical composition of Buddhist nun.
Table 1: transfer of the source of people breast cancer tumour strain HBC-5 in mouse lung
Table 2: transfer of the source of people breast cancer tumour strain HBC-5 in mouse lung
Table 3: transfer of the source of people breast cancer tumour strain HBC-5 in mouse lung
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Claims (6)
1. a kind of antitumor medicine composition, which is characterized in that comprising certain a effective amount of glutamine enzyme inhibitor and
VEGF signal path correlation targeted drug；The glutamine enzyme inhibitor is BPTES (Bis-2- (5-
Phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide) or GI-003；The chemical name of GI-003
For 2- phenyl-N- (5- (4- ((5- (2- phenylacetamido) -1,3,4- thiadiazoles -2- base) amino) piperidin-1-yl) -1,3,
4- thiadiazoles -2- base) acetamide, shown in structure such as formula (VIII):
The VEGF signal path correlation targeted drug is bevacizumab.
2. pharmaceutical composition described in claim 1, which is characterized in that constituent can simultaneously, separately or order of administration.
3. pharmaceutical composition as described in claim 1 answering in preparation treatment non-small cell lung cancer or the drug of breast cancer
With.
4. a kind of anti-tumor drug preparation, which is characterized in that be using pharmaceutical composition described in claim 1 as activity at
Point, and it is aided with acceptable pharmaceutic adjuvant, carrier and/or excipient, various preparations are made, it is selected from oral solution, capsule and pill, solid
Dispersion, sustained release agent, granule, tablet, injection, ointment, patch, implant.
5. a kind of glutamine enzyme inhibitor GI-003, which is characterized in that the chemical name of GI-003 is 2- phenyl-N- (5- (4-
((5- (2- phenylacetamido) -1,3,4- thiadiazoles -2- base) amino) piperidin-1-yl) -1,3,4- thiadiazoles -2- base) acetyl
Amine, shown in structure such as formula (VIII):
6. glutamine enzyme inhibitor described in claim 5 preparation treat or prevent increase with glutaminase active it is related
Purposes in the drug of illness.
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