Compound with signal transduction and transcriptional activator 3 inhibition activity and application thereof
阅读说明:本技术 具有信号转导与转录激活因子3抑制活性的化合物及其用途 (Compound with signal transduction and transcriptional activator 3 inhibition activity and application thereof ) 是由 李充基 芮相圭 金丙鹤 于 2017-10-31 设计创作,主要内容包括:本发明涉及具有信号转导与转录激活因子3抑制活性的化合物,或其药剂学上可接受的盐、溶剂化物或水合物以及它们的药剂学用途。本发明的化合物有效地抑制与各种疾病相关的信号转导与转录激活因子3的非正常活性,因此,可有用地用于预防及治疗与癌症、自身免疫性疾病、炎症性疾病等相关的各种信号转导与转录激活因子3相关疾病的目的。(The invention relates to a compound with signal transduction and transcriptional activator 3 inhibition activity, or pharmaceutically acceptable salt, solvate or hydrate thereof and pharmaceutical application thereof. The compounds of the present invention effectively inhibit abnormal activities of signal transduction and transcriptional activator 3 associated with various diseases, and thus, are useful for the purpose of preventing and treating various signal transduction and transcriptional activator 3-associated diseases associated with cancer, autoimmune diseases, inflammatory diseases, and the like.)
1. A compound or a pharmaceutically acceptable salt, solvate or hydrate thereof, which is selected from the group consisting of compounds represented by the following chemical formulae 1 to 60:
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2. a pharmaceutical composition for preventing or treating a disease in which signal transduction and transactivator 3 are involved,
comprises the following steps:
(a) a pharmaceutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof; and
(b) a carrier which is acceptable in terms of pharmacy,
the above-mentioned diseases associated with signal transduction and transcription activator factor 3 are selected from the group consisting of cancer, diabetic retinopathy, diabetes mellitus, hemophiliac arthropathy, atherosclerosis, keloid, wound granulation, vascular adhesion, autoimmune diseases, restenosis, intestinal adhesion, cat scratch disease, ulcer, liver cirrhosis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy, organ transplant rejection, glomerulopathy, neurodegenerative diseases and inflammatory diseases.
3. The composition of claim 2, wherein said compound selectively inhibits the activity of signal transduction and transcriptional activator 3.
4. The composition of claim 2, wherein said composition inhibits metastasis of cancer cells.
5. The composition of claim 2, wherein the diseases associated with the dsf 3 are cancers selected from the group consisting of stomach cancer, large intestine cancer, lung cancer, breast cancer, ovarian cancer, liver cancer, bronchial cancer, nasopharyngeal cancer, laryngeal cancer, pancreatic cancer, bladder cancer, colon cancer, cervical cancer, brain cancer, prostate cancer, bone cancer, skin cancer, thyroid cancer, leukemia, lymphoma, adrenocortical cancer, parathyroid cancer, ureteral cancer, glioma, esophageal cancer, small intestine tumor, glioblastoma, brain tumor, and kidney cancer.
6. The composition of claim 2, wherein the disease associated with the activation of transcription factor 3 is selected from the group consisting of alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, adrenal autoimmune disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune oophoritis and orchitis, autoimmune thrombocytopenia, Behcet's disease, bullous pemphigoid, cardiomyopathy, diarrheal dermatitis, chronic fatigue immunodeficiency syndrome, chronic inflammatory demyelinating polyneuropathy, allergic granulomatosis, cicatricial pemphigoid, acral scleroderma, cold agglutinin disease, Crohn's disease, discoid lupus, primary cryoglobulinemia, fibromyalgia-fibromyositis, glomerulonephritis, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura, immunoglobulin A neuritis, juvenile arthritis, lichen planus, lupus erythematosus, meniere's disease, mixed connective tissue disease, multiple sclerosis, type 1 diabetes mellitus or immune-mediated diabetes mellitus, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis, autoimmune polyadaptic syndrome, rheumatoid polymyalgia, polymyositis and dermatomyositis, primary agammaglobulinemia, primary glycaemic liver cirrhosis, psoriasis, psoriatic arthritis, raynaud's phenomenon, Reiter's syndrome, rheumatoid arthritis, sarcoidosis, scleroderma, systemic myotonic syndrome, systemic lupus erythematosus, takayasu's arteritis, temporal arteritis, giant cell arteritis, and combinations thereof, Ulcerative colitis, uveitis, leukoderma and wegener's granulomatosis.
7. The composition of claim 2, wherein the diseases associated with Signaling and transcriptional activator 3 are inflammatory diseases selected from the group consisting of asthma, encephalitis, inflammatory bowel disease, rheumatoid arthritis, chronic obstructive pulmonary disease, allergy, atopic dermatitis, psoriasis, septic shock, pulmonary fibrosis, undifferentiated spondyloarthropathy, Crohn's disease, pancreatitis, dermatitis, undifferentiated arthropathy, arthritis, glomerulonephritis, bronchitis, inflammatory osteolysis, and chronic inflammation caused by viral or bacterial infection.
8. A food composition for preventing or ameliorating a signal transduction and transcription activator factor 3-related disease selected from the group consisting of cancer, diabetic retinopathy, diabetes mellitus, hemophilia arthropathy, atherosclerosis, keloids, wound granulation, vascular adhesion, autoimmune diseases, restenosis, intestinal adhesion, cat scratch, ulcer, liver cirrhosis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy, organ transplant rejection, glomerulopathy, neurodegenerative diseases and inflammatory diseases, comprising the compound or salt thereof according to claim 1 as an active ingredient.
9. A method for preventing or treating a disease in which signal transduction and transcriptional activator 3 are involved,
comprising administering to a subject (a) a pharmaceutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (b) a pharmaceutically acceptable carrier,
the above-mentioned diseases associated with signal transduction and transcription activator factor 3 are selected from the group consisting of cancer, diabetic retinopathy, diabetes mellitus, hemophiliac arthropathy, atherosclerosis, keloid, wound granulation, vascular adhesion, autoimmune diseases, restenosis, intestinal adhesion, cat scratch disease, ulcer, liver cirrhosis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy, organ transplant rejection, glomerulopathy, neurodegenerative diseases and inflammatory diseases.
10. Use of a compound according to claim 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof as a pharmaceutical composition for preventing or treating a signal transduction and transcription activator 3-related disease selected from the group consisting of cancer, diabetic retinopathy, diabetes mellitus, hemophilia arthropathy, atherosclerosis, keloids, wound granulation, vascular adhesion, autoimmune diseases, restenosis, intestinal adhesion, cat scratch disease, ulcer, liver cirrhosis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy, organ transplant rejection, glomerulopathy, neurodegenerative diseases and inflammatory diseases.
11. Use of the compound according to claim 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof as a food composition for preventing or improving a signal transduction and transcription activator 3-related disease selected from the group consisting of cancer, diabetic retinopathy, diabetes mellitus, hemophilia arthropathy, atherosclerosis, keloids, wound granulation, vascular adhesion, autoimmune diseases, restenosis, intestinal adhesion, cat scratch disease, ulcer, liver cirrhosis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy, organ transplant rejection, glomerulopathy, neurodegenerative diseases and inflammatory diseases.
Technical Field
The invention relates to a compound with signal transduction and
Background
In previous studies, the present inventors confirmed the fact that Signal Transducer and Activator of Transcription 3 (STAT 3) plays an important role in the stability of Hypoxia Inducible Factor-1alpha (HIF-1 alpha) protein, and interacts with Hypoxia Inducible Factor-1alpha of human renal cancer cells to improve Hypoxia Inducible Factor-1-mediated expression of Vascular Endothelial Growth Factor (VEGF) (Jung JE, et al. EB J.19, 1296-1298 (2005)). Furthermore, caffeic acid derivatives effectively inhibit the expression of vascular endothelial growth factor gene by inhibiting the activity of tyrosine-705 of signal transduction and transcriptional activator 3 (Jung JE, et al. Carcinogenesis.28, 1780-1787 (2007)). Furthermore, the transcriptional activity of cyclin D1(cyclin D1), which is known to regulate cell division and cell proliferation, is regulated depending on the activity of the signal transduction and
Signal transduction and transcription activators s (stats) are transcription factors activated by phosphorylation of tyrosine protein Kinase (JAK), which is one of Receptor tyrosine kinases (Receptor tyrosine kinases), Epidermal Growth Factor Receptor (EGFR), Platelet-derived Growth Factor Receptor (PDGFR), and the like (Darnell jejr. science.277, 1630-. Signal transduction activated by phosphorylation forms dimers (dimer) with transcriptional activators s, which move to the inside of the nucleus to bind to the vicinity of the promoter of the target gene to induce transcription of various genes associated with diseases (Darnell JE Jr. science.277, 1630-. Signal transducer and activator of
Throughout this specification, reference is made to and citations of a number of papers and patent documents. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to more clearly describe the state of the art to which this invention pertains and the contents of this invention.
Disclosure of Invention
Technical problem
The present inventors have made efforts to develop novel compounds having selective inhibitory activity against signal transduction and
Accordingly, an object of the present invention is to provide compounds of the following
It is still another object of the present invention to provide a pharmaceutical composition for preventing or treating diseases in which signal transduction and
It is another object of the present invention to provide a food composition for preventing or improving diseases in which signal transduction and
Other objects and advantages of the present invention will become more fully apparent from the following detailed description of the invention, the appended claims and the accompanying drawings.
Technical scheme
According to an embodiment of the present invention, there is provided a compound selected from the group consisting of compounds represented by the following
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the present inventors have made efforts to develop novel compounds having selective inhibitory activity against signal transduction and
The present invention includes not only compounds selected from the group consisting of the compounds represented by
The term "pharmaceutically acceptable salt" in the present specification is a dosage form of a compound that does not induce severe irritation to the organism to which the compound is administered and does not impair the biological activity and physical properties of the compound. The above-mentioned pharmaceutical salts can be obtained by reacting the compound of the present invention with an inorganic acid such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, a sulfonic acid such as methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and the like, an organic carbonic acid such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, decanoic acid, isobutyric acid, malonic acid, succinic acid, phthalic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid and the like. The compound of the present invention can also be obtained by reacting a compound of the present invention with a base to form a salt such as an alkali metal salt such as an ammonium salt, a sodium salt, or a potassium salt, a salt such as an alkaline earth metal salt such as a calcium salt or a magnesium salt, an organic base salt such as dicyclohexylamine, N-methyl-D-glucosamine, or tris (hydroxymethyl) methylamine, and an amino acid salt such as arginine or lysine.
The term "hydrate" in the present specification is a compound of the present invention or a salt thereof comprising a stoichiometric (stoichiometric) or non-stoichiometric (non-stoichiometric) amount of water bound by non-covalent intermolecular forces (non-covalent intermolecular forces), and the term "solvate" is a compound of the present invention or a salt thereof comprising a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Preferred solvents in connection therewith are volatile solvents, non-toxic solvents and/or solvents suitable for administration to humans.
According to still another embodiment, the present invention provides a pharmaceutical composition for preventing or treating a disease in which signal transduction and
The term "prevention" in the present specification means all actions of inhibiting or delaying the development of a disease in which signal transduction and
The term "a disease in which signal transduction and
According to an embodiment of the present invention, the cancer is selected from the group consisting of stomach cancer, large intestine cancer, lung cancer, breast cancer, ovarian cancer, liver cancer, bronchial cancer, nasopharyngeal cancer, laryngeal cancer, pancreatic cancer, bladder cancer, colon cancer, cervical cancer, brain cancer, prostate cancer, bone cancer, skin cancer, thyroid cancer, leukemia, lymphoma, adrenal cortex cancer, parathyroid cancer, ureter cancer, glioma, esophageal cancer, small intestine tumor, glioblastoma, brain tumor, and renal cancer.
According to an embodiment of the invention, the autoimmune disease is selected from the group consisting of alopecia areata (alpoteca greata), ankylosing spondylitis, antiphospholipid syndrome, autoimmune addison's disease, adrenal autoimmune disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune oophoritis and orchitis, autoimmune thrombocytopenia, behcet's disease, bullous pemphigoid, cardiomyopathy, diarrheal dermatitis (celiac muscle-dermatitis), chronic fatigue immunodeficiency syndrome, chronic inflammatory demyelinating polyneuropathy, allergic granulomatosis (Churg-strauss syndrome), cicatricial pemphigoid, terminal scleroderma syndrome (CREST syndrome), cold agglutinin disease, Crohn's disease, discoid lupus, primary cryoglobulinemia, fibromyalgia-fibromyositis, glomerulonephritis, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura, immunoglobulin A (IgA) neuritis, juvenile arthritis, lichen planus, lupus erythematosus, meniere's disease, mixed connective tissue disease, multiple sclerosis, type 1 diabetes mellitus or immune-mediated diabetes mellitus, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis, autoimmune polyadenylic syndrome, rheumatoid polymyalgia, polymyositis and dermatomyositis, primary agammaglobulinemia, primary hyperglycemic liver cirrhosis, psoriasis, psoriatic arthritis, Raynaud's phenomenon, Reiter's syndrome, rheumatoid arthritis, sarcoidosis, scleroderma, systemic myotonic syndrome, systemic lupus erythematosus, Takayasu's arteritis, Temporal arteritis, giant cell arteritis, ulcerative colitis, uveitis, leukoderma, and wegener's granulomatosis.
According to an embodiment of the present invention, the inflammatory disease is selected from the group consisting of asthma, encephalitis (encephalitis), inflammatory enteritis, rheumatoid arthritis, chronic obstructive pulmonary disease, allergy, atopic dermatitis, psoriasis, septic shock, pulmonary fibrosis, undifferentiated spondyloarthropathy, crohn's disease, pancreatitis, dermatitis, undifferentiated arthropathy, arthritis, glomerulonephritis, bronchitis, inflammatory osteolysis, and chronic inflammation caused by viral or bacterial infection.
According to an embodiment of the present invention, the compounds represented by
The compositions of the present invention comprise a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier included in the composition of the present invention includes lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, mineral oil, etc., which are generally used for formulation, but is not limited thereto. In addition to the above ingredients, the pharmaceutical composition of the present invention may further include lubricants, humectants, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives and the like. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington's Pharmaceutical Sciences (19th ed., 1995).
The pharmaceutical composition of the present invention can be administered orally or parenterally, and in the case of parenteral administration, it can be administered by intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, and the like.
The appropriate dosage of the pharmaceutical composition of the present invention may be prescribed according to factors of formulation method, administration mode, patient age, body weight, sex, disease state, diet, administration time, administration route, excretion rate and reaction sensitivity. For example, the dosage of the pharmaceutical composition of the present invention is 0.0001 to 100mg/kg for 1 day.
The pharmaceutical composition of the present invention can be prepared in a unit volume form or added to a multi-volume container by formulating it with a pharmaceutically acceptable carrier and/or excipient according to a method easily implemented by those skilled in the art to which the present invention pertains. In this case, the formulation may be in the form of a solution, suspension, syrup or emulsion in an oil medium or an aqueous medium, or in the form of an extractant, powder, granule, tablet or capsule, and may further include a dispersant or a stabilizer.
According to another embodiment, the present invention provides a food composition for preventing or improving a signal transduction and transcription activator 3-associated disease, comprising a compound selected from the group consisting of the compounds represented by the
The food composition may be any food in the forms of health functional food, nutritional supplement, medical food (pharmafood), health food, nutritional preparation (nutraceutical), special food, food additive, etc., but is not limited thereto, and examples thereof include meat, sausage, bread, chocolate, confectionery, snack, biscuit, pizza, instant noodles, other pasta, chewing gum, milk products including ice cream, various soups, beverages, tea, oral liquid, alcoholic beverage, vitamin complex, etc.
The food composition of the present invention comprises ingredients that are normally added when manufacturing a food, for example, comprising proteins, carbohydrates, fats, nutrients, seasonings and flavoring agents. Examples of the above-mentioned carbohydrates are conventional sugars and sugar alcohols, i.e., monosaccharides such as glucose and fructose, disaccharides such as maltose, sucrose and oligosaccharides, polysaccharides such as dextrin and cyclodextrin, sugar alcohols such as xylitol, sorbitol and erythritol. As the flavoring agent, natural flavoring agents [ african sweet fruit essence, stevia extract (e.g., rebaudioside a, glycyrrhizin, etc.) ] and synthetic flavoring agents (saccharin, aspartame, etc.) can be used.
The food composition of the present invention may contain, in addition to the above-mentioned ingredients, various nutrients, vitamins, minerals (electrolytes), dietary ingredients, flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents, reinforcing agents (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonation agents for carbonated beverages, and the like. For example, when the food composition of the present invention is prepared as an oral liquid, citric acid, liquid fructose, granulated sugar, glucose, acetic acid, malic acid, fruit juice, various plant extracts, and the like may be contained in addition to the active ingredient of the present invention.
In still another embodiment, the present invention provides a cosmetic composition (functional cosmetic composition) for preventing or improving a disease in which signal transduction and
The above cosmetic composition may be prepared in any dosage form conventionally prepared in the art, comprising ingredients commonly used for the preparation of cosmetics, in addition to the active ingredients, and for example, may include common adjuvants such as antioxidants, stabilizers, solubilizers, vitamins, pigments, and perfumes.
As still another embodiment, the present invention provides a method for preventing or treating a disease in which signal transduction and
As still another embodiment, the present invention provides a use of a compound selected from the group consisting of the compounds represented by
As still another embodiment, the present invention provides a use of a compound selected from the group consisting of the compounds represented by
As still another embodiment, the present invention provides a use of a compound selected from the group consisting of the compounds represented by
ADVANTAGEOUS EFFECTS OF INVENTION
The features and advantages of the invention are as follows:
(i) the present invention provides novel compounds having signal transduction and
(ii) The compound of the present invention can be used as an active ingredient for the preparation of pharmaceutical, functional cosmetic (cosmeceutical), cosmetic, functional food (neutraceutical) or food compositions.
(iii) The compounds of the present invention are effective in inhibiting abnormal activities of signal transduction and
Drawings
FIGS. 1a to 1g show a model using a binding molecule structure model related to Drosophila and human cancer cells and SH2 domain binding to
FIGS. 2a and 2b show that the ODZ17690 compound of the invention has an excellent effect of selectively inhibiting signal transduction and the activity of
FIGS. 3a to 3c
FIGS. 4a to 4h show binding molecule structure models of ODZ10117 compounds associated with SH2 domain that bind to signal transduction and
FIGS. 5a to 5c show that ODZ10117 compound inhibits the activity of signal transduction and
FIGS. 6a and 6b show that ODZ10117 compound inhibits the activity of signal transduction and transcription activator 92E (mammalian signal transduction and transcription activator) in Drosophila cells.
Fig. 7a to 7d show that ODZ10117 compounds inhibit the activity of signal transduction and
Fig. 8a to 8c show that ODZ10117 compounds inhibit the activity of signal transduction and
Fig. 9a to 9d show that ODZ10117 compounds inhibit signal transduction and
Fig. 10 shows that ODZ10117 compounds inhibit signal transduction and transcriptional activator 3-dependent cell survival in human glioblastoma.
FIGS. 11a to 11e show that ODZ10117 compounds inhibit proliferation of U87-MG cells and MDA-MB-231 cells, inducing cell death.
FIGS. 12a to 12d show that ODZ10117 compounds inhibit the migration and infiltration of U87-MG cells and MDA-MB-231 cells.
Fig. 13a to 13d show the tumor size of ODZ10117 compounds that inhibited growth in xenograft mice.
Fig. 14a to 14d show signal transduction and activator of
Fig. 15a and 15b show the signal transduction and activator of
FIG. 16 shows the signal transduction and
Detailed Description
The present invention will be described in more detail below with reference to examples. It will be apparent to those skilled in the art that these examples are merely for specifically illustrating the present invention and the scope of the present invention is not limited to these examples according to the gist of the present invention.
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