CN102766103B - 2-sulfo-4-amino-1-naphthol derivative and preparation method and application thereof - Google Patents
2-sulfo-4-amino-1-naphthol derivative and preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the field of pharmaceutical chemicals, and in particular relates to a 2-sulfo-4-amino-1-naphthol derivative and pharmaceutically acceptable salt thereof, a solvate of the derivative, and a solvate of the pharmaceutically acceptable salt. The invention also relates to a preparation method, a medical composition and application of the 2-sulfo-4-amino-1-naphthol derivative. The 2-sulfo-4-amino-1-naphthol derivative has a good tyrosine kinase inhibiting effect and low toxicity and has great significance for the clinical treatment of tumor.
Description
Technical field
The invention belongs to field of medicine and chemical technology, be specifically related to class 2-sulfo--4-amido-1-naphthol derivative, its pharmacy acceptable salt, the solvate of described derivative and the solvate of described pharmacy acceptable salt.The invention still further relates to the purposes of preparation method, its pharmaceutical composition and the described derivative of described 2-sulfo--4-amido-1-naphthol derivative.
Background technology
Tumour be serious threat human life and healthy principal disease it, according to World Health Organization's statistics, the patient approximately 6,900,000 of tumour is died from the whole world every year.Due to the change of living environment and life habit, under the effect of poor environment and some unfavorable factors, the M & M of tumour is progressively ascendant trend in recent years.
The treatment of tumour was realized by finding tumour destruction in the past, now along with deepening continuously to cell signaling Study of way, it is more and more deep that people understand the effect of the oncogene of tumour cell inside and antioncogene, the antitumor drug new for the specific molecular shot design of tumour more and more receives publicity, become the hot fields of research, and that anti-tumor drugs targeting has also been applied to as a kind of new methods for the treatment of is clinical, and obtained in recent years significant progress.Now known, propagation, differentiation, migration and the apoptosis of protein tyrosine kinase (PTK) signal path and tumour cell has substantial connection (Sun L., et al., Drug Discov Today, 2000,5,344-353), utilizing protein tyrosine kinase inhibitor to disturb or block Tyrosylprotein kinase path can be for oncotherapy (Fabbro D., et al., Curr Opin Pharmacol, 2002,2,374-381).
Protein tyrosine kinase (PTK) is the cancer protein that plays an important role in normal and abnormality proliferation process and the member in proto-protein family, it is a kind of a kind of enzyme that can optionally make the tyrosine residues phosphorylation of different substrates, γ-phosphate of their catalysis ATP is transferred on the tyrosine residues of many key proteins, makes phenolic hydroxyl group phosphorylation.Protein tyrosine kinase is divided into receptor tyrosine kinase (RTK), (Robinson D.R., the et al. such as nonreceptor tyrosine kinase and IR and Janus kinases, Oncogene, 2000,19,5548-5557), wherein majority is receptor type tyrosine kinase (RTK).Receptor tyrosine kinase (RTK) is that a class has endogenous protein Tyrosylprotein kinase, participates in the regulation and control of various kinds of cell activity, in the conduction of the mitogenesis signal copying at active cell, has extremely important status, is regulating and controlling the Proliferation and differentiation of cell.All RTK belong to I type membranin, and its molecule has similar topological framework: the outer ligand binding domain of large glycosylated born of the same parents, a hydrophobic single cross-film district, and kinase catalytic structural domain of intracellular tyrosine and regulating and controlling sequence.The combination of part causes the kinase activation of the inner Coded of recipient cell to activate, and makes the crucial tyrosine phosphorylation in target protein, causes the transduction of hyperplasia signal spans cytoplasmic membrane.
The peptide chain-ordering that most cells growth factor receptors contains Tyrosylprotein kinase, in many tumours, crossing of visible different tyrosine kinase receptors expressed or activated.According to the similarity of peptide chain-ordering and structural feature thereof, these acceptors are divided into again some families: 1) Epidermal Growth Factor Receptor Family, comprise EGFR, HER-2, HER-3, HER-4 etc., and the high expression level of this receptoroid is common in epithelial cell tumour; 2) Insulin Receptor Family, comprises insulin receptor, IGF-1 (IGF-R) and Regular Insulin associated receptor (IRR) etc., the high expression level of common this receptoroid in leukemia; 3) Platelet Derived Growth Factor Receptor Family (PDGFR), comprises PDGFR-α, PDGFR-β, CSF-1R, c-Kit etc., this receptoroid common high expression level in cerebral tumor, leukemia; 4) fibroblast growth factor acceptor (FGFR), comprises FGFR-1, FGFR-2, FGFR-3, FGFR-4 etc., and this receptoroid plays an important role aspect vasculogenesis; 5) vascular endothelial growth factor receptor (VEGFR), comprises VEGFR-1, VEGFR-2, VEGFR-3, is the important positivity regulatory factor of vasculogenesis.Tyrosine kinase receptor overexpression in dissimilar tumour, causes abnormal signal in its cell to activate, and causes cell transformation, constantly breeds, promote generation, the development of tumour, inhibited apoptosis, therefore, target tyrosine kinase signal approach is good antitumor strategy.
Vascular endothelial growth factor (VEGF) be Main Function in the somatomedin of vascular endothelial cell, have and promote endothelial cell proliferation, increase several functions (Hanks S.K., the et al. such as microvascular permeability, induction of vascular generation, FASEB, 1995,9,576-596).At present, VEGF family mainly comprises 6 member: VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E and PDF.Wherein, VEGF-C is a newcomer of VEGF family, by the separation and purification from PC-3 PC3 of the use Flt4 affinity chromatographies such as Joukov obtain (Joukov V., et al., EMBO J, 1996,15,290-298).VEGF-C can activate the Flt4 on lymphatic endothelial specifically, therefore, and the VEGF-C B cell growth factor that is otherwise known as.VEGF-C has the dual function that stimulates blood vessel and lymphatic vessel to generate, and its acceptor VEGFR-2 is mainly distributed in vascular endothelial cell, by being combined with VEGFR-2, promotes vascular endothelial cell proliferation, migration and angiogenic growth.The formation of tumour and development substantially can be divided into two stages, i.e. clone's property multiplicative stage of tumour cell and the vascularization that comes next promotes tumour to continue the stage of growth.VEGF acts on self existing vasoganglion endotheliocyte, makes its differentiation and forms new blood vessel.Neovascularity not only provides basis for the exchange of substance of tumour cell, also can some cytokines of paracrine promotes the propagation of tumour cells; Simultaneously the structural pipe wall due to new vessel lacks integrity, between endotheliocyte, connect loose, basilar membrane thickness differ, rupture or lack as, oncocyte is easy to intravasation chamber and blood invasion and attack and transfer occurs.Thereby the growth of VEGF and tumour and transfer relationship close.VEGF can detect in the majority tissue of healthy human body, but expression amount is very micro-, in many tumours, especially in noumenal tumour, there is high expression level, as: (Samoto K., et al.Cancer Res in liver cancer, cerebral tumor, mammary cancer, lung cancer and renal carcinoma tissue, 1995,55,1189-1193; Ferrara N..Curr Opin Biotech, 2000,11,617-624; Shiladitya S., et al.Nature, 2005,436:568-572).Due to growth and the dependency of transfer to new vessel of solid tumor, so VEGF is the more satisfactory target site of blocking-up solid tumor vascularization.There are two viewpoints to promote the research of tumour angiogenesis inhibitor, first: the general new vessel of health adult is less, therefore it has been generally acknowledged that angiogenesis inhibitor side effect is less; Second: in angiogenesis, related endotheliocyte is normal cell, there is not genomic instability, this just means that angiogenesis inhibitor treatment not too can produce resistance.VEGFR is a kind of diffusible blood vessel endothelium specificity mitogen and Angiogenesis factor receptors, in physiological and pathologic vessels forming process, plays a crucial role, and can suppress endothelial cell apoptosis.This family has 3 members, i.e. VEGFR1, VEGFR2, VEGFR3.Generally believe that at present it is by VEGF and the vegf receptor 2(VEGFR-2 that is positioned at Surface of Vascular Endothelial Cells that VEGF induction of vascular generates) in conjunction with institute, mediate, VEGF causes after being combined with VEGFR-2 that VEGFR-2 forms dimer and lures tyrosine kinase mediated phosphorylation into, the one-step activation of the going forward side by side downstream signal Signal Transduction Pathways of being correlated with.
Small molecule tyrosine kinase inhibitors is as new anti-tumor drugs targeting, and for a fan new window has been opened in treatment and the prevention of tumour, and its side effect is slight, has good tolerance.Although existing more than 10 small molecule tyrosine kinase inhibitors is that clinical cancer therapy has been made very large contribution at present, but still need to find that some have the other compound of the pharmacological characteristics of better activity in vivo and/or improvement than existing tyrosine kinase inhibitor.Therefore develop new improved or more efficient tyrosine kinase inhibitor, more in depth understand relation between such medicine and known target protein with and the mechanism of bringing into play antitumor action clinical therapy of tumor is had great importance.
At present, the angiogenesis inhibitor of target VEGF and acceptor thereof has: VEGF non-activity mutant, VEGF inverted defined gene, soluble VEGF-receptor, VEGF monoclonal antibody and vegf receptor tyrosine kinase (RTK) inhibitor etc.Wherein vegf receptor tyrosine kinase inhibitor belongs to micromolecular inhibitor, and there is oral easy absorption, little, the applicable long-term prescription of dosage, synthesize the advantages such as easy, be the angiogenesis inhibitor that a class gets a good chance of.In recent years, multiple target had successfully been pushed to the treatment of market for various tumours in the medicine of VEGFR as Sunitinib, Sorafenib, Pazopanib etc.Although these angiogenesis inhibitors have very large advantage, the problems such as resistance, untoward reaction and toxicity that practical application still exists that Partial tumors is strong to the newborn dependency of blood vessel, the compensatory of sudden change and tumor signal conduction causes.Therefore further exploitation selectivity small molecules RTK inhibitor stronger, that activity is higher and toxicity is less is still very necessary.
Summary of the invention
The object of the invention is to find the new compound that there is high tyrosine kinase inhibitory activity and there is low toxicity.
The inventor be take the crystalline structure of VEGFR-2 Tyrosylprotein kinase and as basis, is carried out screening compound, selects the compound structure that has fine combination with receptor protein, and has synthesized these compounds by chemical process.In the biological test and activity rating of these compounds, this compounds has shown the new one-tenth of good inhibition blood vessel and antitumor action.
The discovery that the inventor is surprised, has the 2-sulfo--4-amino-1-naphthol derivative shown in general formula I and has unexpected high tyrosine kinase inhibitory activity.The present invention is based on this discovery and be accomplished.
One aspect of the present invention relates to 2-sulfo--4-amido-1-naphthol derivative, its pharmacy acceptable salt, the solvate of described derivative or the solvate of described salt shown in formula I,
Formula I
Wherein,
L is linking group, is selected from Xuan Zi – SO
2-,-CO-Huo – CONH-;
R
1be selected from aryl, heteroaryl, the C1-6 alkyl that cycloalkyl, Heterocyclylalkyl, aryl replace, the C1-9 alkyl that heteroaryl replaces, the C2-6 thiazolinyl that aryl replaces, the C2-4 alkynyl that the C2-4 alkynyl that aryl replaces, heteroaryl replace; Described aryl, heteroaryl, cycloalkyl, Heterocyclylalkyl can optionally be replaced by one or more following groups: alkyl, alkoxyl group, halo C1-8 alkyl, halo C1-8 alkoxyl group, thiazolinyl, alkynyl, hydroxyl, halogen, nitro, cyano group, C1-6 alkyl-carbonyl, C1-8 alkoxy carbonyl, halo C1-6 alkoxy carbonyl, halo C1-6 alkoxy carbonyl; Preferably, described aryl, heteroaryl, cycloalkyl, Heterocyclylalkyl are optionally replaced by one or more following groups: C1-4 alkyl, C1-4 alkoxyl group, halogenated c1-4 alkyl, halogenated c1-4 alkoxy, halogen, nitro, cyano group, hydroxyl, C1-4 alkoxy carbonyl, halogenated c1-4 alkoxy carbonyl;
R
2be selected from hydrogen, hydroxyl, C1-4 alkoxyl group, halogenated c1-4 alkoxy;
R
3be selected from hydrogen, hydroxyl, C1-4 alkoxyl group, halogenated c1-4 alkoxy;
R
2, R
3preferably be all hydrogen atom or methoxy group;
R
4be selected from and replace or unsubstituted aryl, replacement or unsubstituted heteroaryl;
And, when L is-SO
2-time, R
4only be selected from and replace or unsubstituted 7H-purine-6-base.
2-sulfo--4-amido-1-naphthol derivative shown in formula I, the solvate of its pharmacy acceptable salt, described derivative or the solvate of described salt, wherein, R
4preferred 1H-1,2,4-triazole-5-base, 5-methyl isophthalic acid, 3,4-thiadiazoles-2-base, 1,3,4-thiadiazoles-2-base, 1-methyl isophthalic acid H-tetrazole-5-base, 7H-purine-6-base;
And, when L is-SO
2-time, R
4be selected from and replace or unsubstituted 7H-purine-6-base; Preferably, R
47H-purine-6-the base that is selected from 7H-purine-6-base or is replaced arbitrarily by one or more following groups: alkyl, alkoxyl group, haloalkyl, halogenated alkoxy, cyano group, hydroxyl, halogen, nitro, thiazolinyl, alkynyl, carbonyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl.
The term using in the present invention " alkyl " refers to saturated straight or branched monovalence alkyl, there is 1-8 carbon atom (being C1-8 alkyl), preferred 1-6 carbon atom (being C1-6 alkyl), 1-4 carbon atom (being C1-4 alkyl) or 1-3 carbon atom (being C1-3 alkyl).The example of " alkyl " includes but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, n-pentyl, neo-pentyl, n-hexyl, 2-methyl amyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl etc.
Term used herein " halogen " refers to fluorine, chlorine, bromine or iodine, and preferred halogen group is fluorine, chlorine or bromine.
Term used herein " haloalkyl " refers to or polysubstituted the present invention defined alkyl monosubstituted by the defined halogen of the present invention.Include but not limited to-CF of the example of " haloalkyl "
3,-CHF
2,-CH
2cCl
3deng.
Term used herein " halogenated alkoxy " refers to or polysubstituted the present invention defined alkoxyl group monosubstituted by the defined halogen of the present invention.Include but not limited to-OCF of the example of " haloalkyl "
3,-OCHF
2,-OCH
2cCl
3deng.
Term used herein " aryl " refers to the aromatic carbocyclyl groups of 5-14 the carbon atom with a monocycle or a plurality of fused rings.Described aryl preferably has 5-10,5-8 or 5-6 or 6 carbon atoms.The example of " aryl " includes but not limited to phenyl, naphthyl and anthryl etc.
Term used herein " heteroaryl " refers to the heteroaromatic rings group with 5-14 member, comprises monocycle heteroaromatic rings and polycyclic aromatic ring, and wherein monocyclic aromatic ring and one or more other aromatic rings condense.Heteroaryl has one or more choosings independently from the ring hetero atom of N, O and S.What in term used herein " heteroaryl " scope, also comprise is the group that wherein aromatic ring and one or more non-aromatic ring (carbocyclic ring or heterocycle) condense, and wherein linking group or point are positioned on aromatic ring." heteroaryl " example includes but not limited to pyridyl, pyrimidyl, imidazolyl, pyrryl, pyrazolyl, oxazolyl, thiazolyl, furyl, benzimidazolyl-, benzothienyl, benzofuryl, indyl, benzothiazolyl, benzoxazolyl, quinolyl etc.
The term using in the present invention " thiazolinyl " refers to have 2-8 carbon atom, the preferred monovalence ethylenically unsaturated hydrocarbons base of 2-6 carbon atom, they can for straight or branched and there is at least 1 carbon-carbon double bond.Concrete thiazolinyl includes but not limited to vinyl, n-propenyl, pseudoallyl, butenyl etc.
The term using in the present invention " alkynyl " refers to have 2-8 carbon atom, the preferred monovalence acetylene series unsaturated alkyl of 2-6 carbon atom, they can for straight or branched and there is at least 1 carbon carbon triple bond.Concrete alkynyl includes but not limited to ethynyl, propargyl etc.
Pharmacy acceptable salt of the present invention is selected from: hydrochloride, vitriol, mesylate, tosilate, benzene sulfonate, fumarate, maleate, malate, or the solvate of these salt hydrate for example.
2-sulfo--4-amido-1-naphthol derivative of the present invention is preferably from one of following compound:
N-(3-((1H-1,2,4-triazole-5-) sulfenyl)-4-hydroxyl naphthalene-1-yl) naphthalene-2-methane amide;
N-(3-((1H-1,2,4-triazole-5-) sulfenyl)-4-hydroxyl naphthalene-1-yl)-4-chlorobenzamide;
N-(3-((1H-1,2,4-triazole-5-) sulfenyl)-4-hydroxyl naphthalene-1-yl)-2-nitrobenzamide;
N-(3-((1H-1,2,4-triazole-5-) sulfenyl)-4-hydroxyl naphthalene-1-yl)-4-methoxy benzamide;
(E)-N-(3-((1H-1,2,4-triazole-5-) sulfenyl)-4-hydroxyl naphthyl-1-)-3-(3,4 ,-Dimethoxyphenyl) acrylamide;
N-(3-((1H-1,2,4-triazole-5-) sulfenyl)-4-hydroxyl naphthalene-1-yl)-3-nitrobenzamide;
N-(3-((1H-1,2,4-triazole-5-) sulfenyl)-4-hydroxyl naphthalene-1-yl)-3-methoxy benzamide;
N-(3-((1H-1,2,4-triazole-5-) sulfenyl)-4-hydroxyl naphthalene-1-yl)-3-methyl benzamide;
N-(3-((1H-1,2,4-triazole-5-) sulfenyl)-4-hydroxyl naphthalene-1-yl)-3-(4-nitrophenyl) acrylamide;
N-(3-((1H-1,2,4-triazole-5-) sulfenyl)-4-hydroxyl naphthalene-1-yl)-3-chlorobenzamide;
N-(3-((1H-1,2,4-triazole-5-) sulfenyl)-4-hydroxyl naphthalene-1-yl) the bromo-2-fluorobenzene of-4-sulphonamide;
N-(3-((7H-purine-6-) sulfenyl)-4-hydroxyl naphthalene-1-yl)-3,4-dimethoxy benzsulfamide;
N-(3-((7H-purine-6-) sulfenyl)-4-hydroxyl naphthalene-1-yl)-4-tert.-butylbenzene sulphonamide;
N-(3-((7H-purine-6-) sulfenyl)-4-hydroxyl-6,7-dimethoxy-naphthalene-1-yl)-3,4-dimethoxy benzsulfamide;
N-(3-((7H-purine-6-) sulfenyl)-4-hydroxyl-6,7-dimethoxy-naphthalene-1-yl)-2,6-dichlorobenzene sulphonamide.
Another aspect of the present invention relates to a kind of pharmaceutical composition, it comprises above-mentioned 2-sulfo--4-amido-1-naphthol derivative, its pharmacy acceptable salt, the solvate of described derivative or the solvate of described pharmacy acceptable salt, and optional one or more pharmaceutically acceptable carrier and/or auxiliary materials.
A further aspect of the invention relates to the preparation method of above-mentioned 2-sulfo--4-amido-1-naphthol derivative, comprises the steps:
1) with R
2, R
3the 1-nitro-naphthalene replacing is raw material, take DMSO and water as mixed solvent, react the contraposition introducing hydroxyl at nitro under potassium hydroxide exists with peroxy tert-butyl alcohol, then with palladium carbon, makes catalyzer hydro-reduction and obtain intermediate (II);
2) by intermediate (II) and R
1the acyl chlorides replacing or SULPHURYL CHLORIDE or isocyanic ester at room temperature react 8-12 hour, obtain key intermediate (III), then obtain quinoid intermediate (IV) through sodium periodate oxidation;
3) by quinoid intermediate (IV) and R
4there is Michael reaction and obtain ultimate aim product in SH:
Wherein, L, R
1, R
2, R
3, R
4as previously mentioned; Described room temperature refers to 20-30 ℃.
Invention also relate to above-mentioned 2-sulfo--4-amido-1-naphthol derivative, its pharmacy acceptable salt, the solvate of described derivative or the purposes of the solvate of described salt in preparing tyrosine kinase inhibitor.
Also aspect of the present invention relate to above-mentioned 2-sulfo--4-amido-1-naphthol derivative, its pharmacy acceptable salt, the solvate of described derivative or the solvate of described salt for the preparation of in treating and/or preventing Mammals with the medicine of receptor tyrosine kinase relative disease in purposes.Particularly, described Mammals is the mankind.
Above-mentioned 2-sulfo--4-amido-1-naphthol derivative, its pharmacy acceptable salt, the solvate of described derivative or the solvate of the described salt purposes in the medicine of the tumour being mediated by receptor tyrosine kinase for the preparation for the treatment of or assisting therapy and/or prevention Mammals or the tumor cell proliferation being driven by receptor tyrosine kinase and migration that also relates to of the present invention.Particularly, described Mammals is the mankind.
According to the present invention, can expect that the compounds of this invention can be used for treating the responsive cancer of the Tyrosylprotein kinases such as VEGFR or PDGFR completely, as VEGFR, the tumour that PDGFR high expression level and VEGF drive, comprise that noumenal tumour is as bile duct, bone, bladder, brain/central nervous system, breast, knot rectum, uterine endometrium, stomach, head and neck, liver, lung (especially nonsmall-cell lung cancer), neurone, esophagus, ovary, pancreas, prostate gland, kidney, skin, testis, Tiroidina, the cancer of uterus and vulva etc., with non-noumenal tumour as leukemia, multiple myeloma or lymphoma etc.Derivative of the present invention can regulate the activity of protein kinase, can be for prevention and the treatment of protein kinase dependency cell dysfunction, thus compound of the present invention can also be for preventing and treat the dysfunction that relates to paraprotein kinase activity.
An also aspect of the present invention relates to a kind of method that treats and/or prevents disease relevant to Tyrosylprotein kinase in Mammals, described method comprises 2-sulfo--4-amido-1-naphthol derivative of the present invention, its pharmacy acceptable salt, the solvate of described derivative or the solvate of described salt of using significant quantity, or pharmaceutical composition of the present invention.
Also aspect of the present invention relates in a kind for the treatment of or assisting therapy and/or prevention Mammals (comprising people) method by tyrosine kinase mediated tumour or the tumor cell proliferation being driven by Tyrosylprotein kinase and migration, the method comprises 2-sulfo--4-amido-1-naphthol derivative of the present invention, its pharmacy acceptable salt, the solvate of described derivative or the solvate of described salt of using significant quantity, or pharmaceutical composition of the present invention.
An also aspect of the present invention relates to a kind of tumour of Mammals (comprising people) or method of cancer for the treatment of and/or preventing, described method comprises to the 2-sulfo--4-amido-1-naphthol derivative of the present invention, its pharmacy acceptable salt, the solvate of described derivative or the solvate of described salt that have the administration significant quantity of needs, or pharmaceutical composition of the present invention.Described tumour or cancer comprise VEGFR or the responsive cancer of PDGFR Tyrosylprotein kinase, as the tumour of VEGFR, PDGFR high expression level and VEGF driving, comprise that noumenal tumour is as the cancer of bile duct, bone, bladder, brain/central nervous system, breast, knot rectum, uterine endometrium, stomach, head and neck, liver, lung (especially nonsmall-cell lung cancer), neurone, esophagus, ovary, pancreas, prostate gland, kidney, skin, testis, Tiroidina, uterus and vulva etc., and non-noumenal tumour is as leukemia, multiple myeloma or lymphoma etc.
Below the invention will be further described.
All documents that the present invention quotes from, their full content is incorporated to the present invention by reference, and if when the expressed implication of these documents and the present invention are inconsistent, be as the criterion with statement of the present invention.In addition, various terms and phrase that the present invention uses have the general sense of well known to a person skilled in the art, nonetheless, the present invention still wishes at this, these terms and phrase to be described in more detail and to be explained, the term of mentioning and phrase, if any inconsistent with known implication, are as the criterion with the implication that the present invention was explained.
Term " halogen " or " halo " refer to fluorine, chlorine, bromine and iodine.
In the present invention, when mentioning, the term adopting " alkyl " comprises alkyl, thiazolinyl and alkynyl.
In the present invention, when mentioning, the term adopting " alkyl ", " thiazolinyl " and " alkynyl " have general sense well known in the art, they are hydrocarbyl groups of straight or branched, such as but not limited to methyl, ethyl, propyl group, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, allyl group, propenyl, proyl etc., and described " alkyl ", " thiazolinyl " and " alkynyl " can be referred to as " alkyl " or " chain alkylene ".
In the method for synthetic compound of formula i of the present invention, the various starting material that react used are that those skilled in the art can prepare according to existing knowledge, or can make by the known method of document, or can buy by business.In above reaction scheme, intermediate used, starting material, reagent, reaction conditions etc. all can be made appropriate change according to those skilled in the art existing knowledge.Or, other formula I compound that those skilled in the art also can specifically not enumerate according to the synthetic the present invention of second aspect present invention method.
Formula I compound of the present invention can be used in combination with other activeconstituents, for example, as long as it does not produce other detrimental actions, anaphylaxis.
Active compound shown in formula I of the present invention can be used as cancer therapy drug and uses separately, or can combine use with one or more other antitumor drugs.Combination therapy realizes by each being treated to component while, order or separating administration.
Term used herein " composition " means to comprise the product of respectively specifying composition that comprises specified amount, and any product of the direct or indirect combination results of respectively specifying composition from specified amount.
Compound of the present invention can be used with the form derived from mineral acid or organic acid pharmacy acceptable salt.Word " pharmacy acceptable salt " refers to, within the scope of reliable medical judgment, be suitable for contacting with zootic tissue with the mankind and not occurring excessive toxicity, stimulation, anaphylaxis etc., and with rational effect/risk than the salt matching.Pharmacy acceptable salt is well known in the art.For example, S.M.Berge, et al., J.Pharmaceutical Sciences, have been described in detail pharmacy acceptable salt in 1977,66:1.Described salt can be by making the free alkali functionality of the compounds of this invention and suitable organic acid reaction, in final separation and the preparation of purge process situ or the preparation separately of the compounds of this invention.Representational acid salt includes but not limited to acetate, adipate, alginates, Citrate trianion, aspartate, benzoate, benzene sulfonate, hydrosulfate, vitriol, butyrates, camphorate, camsilate, digluconate, glycerophosphate, Hemisulphate, enanthate, hexanoate, fumarate, hydrochloride, hydrobromate, hydriodate, 2-isethionate (different thiosulphate, isothionate), lactic acid salt, maleate, mesylate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, Pivalate, propionic salt, succinate, tartrate, thiocyanate-, phosphoric acid salt, malate, glutaminate, supercarbonate, tosilate and undecane hydrochlorate.Equally, alkaline nitrogen-containing group can be quaternized with following material: elementary alkyl halide is as the muriate of methyl, ethyl, propyl group and butyl, bromide and iodide; Sulfuric acid dialkyl is as methyl-sulfate, diethyl ester, dibutylester and diamyl ester; Long-chain halogenide is as the muriate of decyl, dodecyl, tetradecyl and octadecyl, bromide and iodide; Arylalkyl halogenide is as bromotoluene and phenethyl bromide and other.
Formula I compound of the present invention also comprises its isomer, raceme, enantiomorph, diastereomer, enantiomorph enriched substance, solvate and ester, formula I compound of the present invention and its isomer, raceme, enantiomorph, diastereomer, enantiomorph enriched substance, solvate and ester can also form solvate, such as hydrate, alcohol adduct etc.Above-claimed cpd can also be prodrug or the form that discharges in vivo described activeconstituents after metabotic change.Selecting and preparing suitable prodrug derivant is technology as well known to those skilled in the art.In general, for object of the present invention, as suitable with non-solvent compound form in the solvate form thereof of water, ethanol etc. with the acceptable solvent of pharmacy.
The active compound amount of gained can change the actual dose level of each activeconstituents in pharmaceutical composition of the present invention, so that can effectively obtain required therapeutic response for concrete patient, composition and administering mode.Dosage level must according to the activity of particular compound, route of administration, the severity of the patient's condition for the treatment of and the patient's to be treated patient's condition and medical history select.But the way of this area is, the dosage of compound is from lower than level that required result for the treatment of requires, increasing gradually dosage, until obtain required effect for obtaining.
When treating and/or preventing or other treatment and/or when prevention for above-mentioned, a kind of the compounds of this invention that treats and/or prevents significant quantity can be applied with pure form, or with the acceptable ester of pharmacy or prodrug forms (in the situation that there are these forms) application.Or described compound can be accepted the pharmaceutical composition administration of vehicle to contain this object compound and one or more medicines.The compounds of this invention that word " treats and/or prevents significant quantity " refers to be applicable to the reasonable effect/risk of any therapeutic treatment and/or prevention than the compound of the q.s for the treatment of obstacle.But the total daily dosage portion that it should be understood that the compounds of this invention and composition must maked decision within the scope of medical judgment reliably by attending physician.For any concrete patient, concrete treatment effective dose level must be determined according to many factors, and described factor comprises the severity of treated obstacle He this obstacle; The activity of the particular compound adopting; The concrete composition adopting; Patient's age, body weight, general health situation, sex and diet; The administration time of the particular compound adopting, route of administration and excretion rate; The treatment time length; The medicine that is used in combination or uses simultaneously with adopted particular compound; And the known similar factor of medical field.For example, the way of this area is, the dosage of compound is from lower than level that required result for the treatment of requires, increasing gradually dosage, until obtain required effect for obtaining.In general, particularly people's dosage can be between 0.001～1000mg/kg body weight/day, for example, between 0.01～100mg/kg body weight/day, for example, between 0.01～10mg/kg body weight/day for Mammals for formula I compound of the present invention.
Use the familiar pharmaceutical carrier of those skilled in the art can be prepared into the pharmaceutical composition containing the compounds of this invention of effective dose.Therefore the present invention also provides the pharmaceutical composition that comprises the compounds of this invention formulated together with one or more nontoxic drug acceptable carriers.That described pharmaceutical composition can be mixed with especially is specially for oral administration with solid or liquid form, for parenteral injection or for rectal administration.
Described pharmaceutical composition can be mixed with many formulations, is convenient to administration, for example, and oral preparations (as tablet, capsule, solution or suspension); Injectable preparation (as injectable solution or suspension, or injectable dried powder, before injection, add injection water to use immediately).In described pharmaceutical composition, carrier comprises: the tackiness agent that oral preparations is used is (as starch, corn normally, wheat or rice starch, gelatin, methylcellulose gum, Xylo-Mucine and/or polyvinylpyrrolidone), thinner is (as lactose, dextrose, sucrose, N.F,USP MANNITOL, sorbyl alcohol, Mierocrystalline cellulose, and/or glycerine), lubricant is (as silicon-dioxide, talcum, stearic acid or its salt, normally Magnesium Stearate or calcium stearate, and/or polyoxyethylene glycol), if and needed, also contain disintegrating agent, as starch, agar, Lalgine or its salt, sodiun alginate normally, and/or effervescent mixture, solubility promoter, stablizer, suspension agent, non-pigment, correctives etc., the sanitas that injectable preparation is used, solubilizing agent, stablizer etc., the matrix that topical formulations is used, thinner, lubricant, sanitas etc.Pharmaceutical preparation can oral administration or parenteral mode (for example intravenously, subcutaneous, intraperitoneal or part) administration, if some drugs is unsettled under stomach condition, can be mixed with enteric coated tablets.
More particularly, pharmaceutical composition of the present invention can by oral, rectum, parenteral, pond, intravaginal, intraperitoneal, part (as by powder, ointment or drops), a mouthful cheek give the mankind and other Mammalss, or give as oral spray or nasal mist.Term used herein " parenteral " refers to comprise intravenously, intramuscular, breastbone is interior, subcutaneous and the administering mode of intra-articular injection and transfusion.
The composition that is suitable for parenteral injection can comprise physiologically acceptable aseptic moisture or non-aqueous solution agent, dispersion agent, suspensoid or emulsion, and for the aseptic powder that reconstitutes sterile injectable solution agent or dispersion agent.Suitable moisture or nonaqueous carrier, thinner, solvent or vectorial example comprise that water, ethanol, polyvalent alcohol (propylene glycol, polyoxyethylene glycol, glycerine etc.), vegetables oil (as sweet oil), injectable organic ester are as ethyl oleate and their suitable mixture.
These compositions also can contain auxiliary material, as sanitas, wetting agent, emulsifying agent and dispersion agent.By various antibacterial agents and anti-mycotic agent, such as parabens, trichloro-butyl alcohol, phenol, Sorbic Acid etc., can guarantee to prevent the effect of microorganism.Also expectation comprises isotonic agent, such as carbohydrate, sodium-chlor etc.By using the material that can postpone absorption, for example aluminum monostearate and gelatin, can reach the prolongation absorption of injectable drug form.
In suspensoid, also can contain suspension agent except active ingredient beyond the region of objective existence, such as ethoxylation i-octadecanol, polyoxyethylene sorbitol and polyoxyethylene sorbitan esters, Microcrystalline Cellulose, the mixture etc. of aluminium hydroxide, wilkinite, agar and tragacanth gum or these materials partially.
In some cases, be the effect of prolong drug, expect to slow down absorption subcutaneous or intramuscularly medicine.This can realize by the liquid suspension of the crystal with poorly water-soluble or amorphous substance.Like this, the absorption rate of medicine depends on its dissolution rate, and dissolution rate can be depending on crystallographic dimension and crystal formation.Or, the delay of the medicament forms of parenteral admin absorb by by this medicine dissolution in or be suspended in oily vehicle and realize.
Injectable depot formulations form can be prepared by form the microcapsule matrix of medicine in as polylactide-PGA (polylactide-polyglycolide) at biodegradable polymer.Can, according to the character of the ratio of medicine and polymkeric substance and the concrete polymkeric substance adopting, drug releasing rate be controlled.The example of other biological degradable polymer comprises poe class (poly(orthoesters)) and polyanhydrides (poly(anhydrides)).Injectable depot formulations also can by pharmaceutical pack is embedded in can be compatible with bodily tissue liposome or micro emulsion in prepare.
Injectable formulation can be for example by filtering or carry out sterilizing by mixing the disinfectant of aseptic solid composite form with bacterial filter, and described solids composition can be dissolved or dispersed in sterilized water or other sterile injectable medium before use.
The compounds of this invention or its composition can be by oral methods or parenteral administration modes.Oral administration can be tablet, capsule, Drug coating, and enteron aisle external application preparation has injection and suppository etc.These preparations are prepared according to method appreciated by those skilled in the art.In order to manufacture tablet, capsule, Drug coating auxiliary material used, it is the auxiliary material of conventional use, for example starch, gelatin, gum arabic, silica, polyoxyethylene glycol, liquid dosage form solvent used is as water, ethanol, propylene glycol, vegetables oil (as Semen Maydis oil, peanut oil, olive wet goods).In the preparation that contains the compounds of this invention, also has other auxiliary material, tensio-active agent for example, lubricant, disintegrating agent, sanitas, correctives and pigment etc.The dosage that contains formula I compound of the present invention in tablet, capsule, Drug coating, injection and suppository is that the compound amount existing in unit dosage form is calculated.In unit dosage form, the general content of formula I compound of the present invention is 1-5000mg, and preferred unit dosage form contains 10-500mg, and preferred unit dosage form contains 20-300mg.Specifically, the solid dosage for oral administration that the present invention can provide comprises capsule, tablet, pill, powder and granule.In this type of solid dosage, active compound can be accepted vehicle or carrier with the medicine of at least one inertia and mix as Trisodium Citrate or Si Liaodengji dicalcium phosphate feed grade and/or following material: a) weighting agent or extender are as starch, lactose, sucrose, glucose, mannitol and silicic acid; B) tackiness agent is as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and Sudan Gum-arabic; C) wetting Agent for Printing Inks is as glycerine; D) disintegrating agent is as agar, calcium carbonate, potato or tapioca (flour), Lalgine, some silicate and sodium carbonate; E) solution retarding agent is as paraffin; F) absorb accelerator as quaternary ammonium compound; G) wetting agent is as hexadecanol and Zerol; H) sorbent material is as kaolin and wilkinite and i) lubricant is as talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate and their mixture.The in the situation that of capsule, tablet and pill, in described formulation, also can comprise buffer reagent.
The solids composition of similar type is used such as lactose and high molecular weight polyethylene glycol etc. of vehicle, also can be used as the weighting material in soft capsule and hard capsule.
The solid dosage of tablet, dragee (dragees), capsule, pill and granule can be prepared together with dressing and shell material other clothing materials as known in enteric coating material and field of medicine preparations.These solid dosages can optionally contain opalizer, and its form also can make it just or preferentially at certain position of enteron aisle optionally with delayed mode release of active ingredients.The example of operable embedding composition comprises polymer substance and wax class.If be applicable to, active compound also can be made into micro-capsule form with one or more above-mentioned vehicle.
Liquid dosage form for oral administration comprises the acceptable emulsion of pharmacy, solution, suspensoid, syrup and elixir.Liquid dosage form also can contain the conventional inert diluent in this area except containing active ingredient beyond the region of objective existence, for example water or other solvents, solubilizing agent and emulsifying agent be ethanol, Virahol, ethyl-carbonate, ethyl acetate, benzylalcohol, peruscabin, propylene glycol, 1,3 butylene glycol, dimethyl formamide, oils (particularly Oleum Gossypii semen, peanut oil, Semen Maydis oil, germ oil, sweet oil, Viscotrol C and sesame oil), glycerine, tetrahydrofurfuryl alcohol (tetrahydrofurfuryl alcohol), polyoxyethylene glycol and the fatty acid ester of sorbitan and their mixture for example.Oral compositions also can comprise auxiliary material except comprising inert diluent, for example wetting agent, emulsifying agent and suspension agent, sweeting agent, correctives and flavouring agent.
The composition of confession rectum or vagina administration is suppository preferably.Suppository can be by by the compounds of this invention and suitable non-irritating excipient or carrier, for example theobroma oil, polyoxyethylene glycol or suppository wax mix to prepare, they are at room temperature solid, therefore but next at body temperature is liquid, can in rectal cavity or vaginal canal, melts and discharge active compound.
Compound of the present invention and composition thereof are also considered for topical.For the local dosage form that gives the compounds of this invention, comprise powder, sprays, ointment and inhalation.Under aseptic condition by active compound and pharmaceutically acceptable carrier and any required sanitas, buffer reagent or propellant mixing.Ophthalmic preparation, eye ointment, powder and solution are also considered within the scope of the present invention.
The compounds of this invention also can liposome form administration.As known in the art, liposome makes with phosphatide or other lipid materials conventionally.Liposome is formed by the single or multiple lift aquation liquid crystal being scattered in water-bearing media.On any nontoxic, physiology that can form liposome, can accept and metabolizable lipid all can be used.The present composition of liposome form, except containing the compounds of this invention, also can contain stablizer, sanitas, vehicle etc.Preferred lipid is natural and synthetic phosphatide and phosphatidylcholine (Yelkin TTS), and they can use separately or together.The method that forms liposome is (referring to for example Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y.(1976) well known in the art, P33).
The inventor is surprised to find, and the 2-sulfo--4-amido-1-naphthol derivative shown in partial structural formula I confirms to have good angiogenesis inhibiting and lower cytotoxicity in the test of rat artery ring and cell toxicity test.From transplanted tumor in nude mice test, also find that these compounds have good activity in vivo, and part of compounds to the restraining effect of tumour and positive control Sorfenib quite or be better than positive control.In addition, from the mortality ratio of animal, analyze, the active compound preferably of part demonstrates the toxicity less than positive control Sorfenib.Specifically, compound of the present invention can be used for the responsive cancers of Tyrosylprotein kinase such as prevention or treatment VEGFR or PDGFR, as the tumour of VEGFR, PDGFR high expression level and VEGF driving, comprise that noumenal tumour is as the cancer of bile duct, bone, bladder, brain/central nervous system, breast, esophagus, ovary, pancreas, prostate gland, kidney, skin, testis, Tiroidina, uterus and vulva etc., and non-noumenal tumour is as leukemia, multiple myeloma or lymphoma etc.
Accompanying drawing explanation
Fig. 1 is Sorafenib, blank and the impact of compound 3 on rat aorta ring vasculogenesis; As can be seen from the figure, the negative control group endotheliocyte well-grown that sprouts; Compound 3 concentration dependent under the concentration of 1-20 μ M suppresses the microvascular new life of rat artery ring; Wherein:
1Soraenib(1 μ M) impact of degree on rat aorta ring vasculogenesis;
2 blanks;
3 compound 3(1 μ M) impact on rat aorta ring vasculogenesis;
4 compound 3(10 μ M) impact on rat aorta ring vasculogenesis;
5 compound 3(20 μ M) impact on rat aorta ring vasculogenesis.
Embodiment
Below by concrete Preparation Example and biological test example, further describe the present invention, still, should be understood to, these embodiment and test example are only used for the use specifically describing more in detail, and should not be construed as for limiting in any form the present invention.
The present invention carries out generality and/or concrete description to the material and the test method that use in test.Although be well known in the art for realizing many materials and the working method that the object of the invention used, the present invention still does to describe in detail as far as possible at this.It will be apparent to those skilled in the art that hereinafter, if not specified, material therefor of the present invention and working method are well known in the art.
In the present invention, unless otherwise indicated, wherein: (i) temperature with degree Celsius (℃) represent, operate under room temperature environment and carry out; More specifically, described room temperature refers to 20-30 ℃; (ii) organic solvent anhydrous sodium sulfate drying, the evaporation of solvent Rotary Evaporators reduction vaporization, bathes temperature not higher than 60 ℃; (iii) for reaction process, thin-layer chromatography (TLC) is followed the tracks of; (iv) end product has satisfied proton magnetic resonance (PMR) spectrum (1H-NMR) and mass spectrum (MS) data.
Embodiment 1 N-(3-((1H-1,2,4-triazole-5-) sulfenyl)-4-hydroxyl naphthalene-1-yl) naphthalene-2-methane amide (compound 1) is synthetic:
Compound 1
1) 4-amino-1-naphthols is synthetic:
1-nitro-naphthalene (0.86g, 5mmol) be dissolved in 13ml DMSO and be cooled to-5 ~ 5 ℃, adding KOH(1.2g, 20mmol) aqueous solution 5ml, stir after 5min, drip peroxy tert-butyl alcohol t-BuOOH(1.8g, 10mmol) DMSO solution 2ml.After the about 2h of stirring at room, react completely, solution is poured in the 1M hydrochloric acid soln of 50ml, faint yellow solid is separated out, and filters, the crude product of 1.38g of weighing after filtration cakes torrefaction to obtain.After recrystallization, obtain sterling 1.20g, faint yellow, fusing point is 166-168 ℃.Gained 4-nitro-1-naphthols (1.89g 10mmol) is dissolved in to 20ml CH
3in OH, pass into hydrogen under 10 normal atmosphere, stirring reaction 12 hours.After TLC detection reaction is complete, filter palladium carbon, steaming desolventizes, and obtains black solid powder crude product 1.32g.After recrystallization, obtaining sterling fusing point is: 198 ℃.
2) N-(4-hydroxyl naphthalene-1-yl)-2-naphthoamide is synthetic:
At-5 ~ 5 ℃, 4-amino-1-naphthols (1.59g, 10mmol) dissolution of solid is containing sodium bicarbonate (2.52g, in tetrahydrofuran (THF)/water 30mmol) (50ml/1ml) mixing solutions, add 2-naphthoyl chloride (2.29g12mmol), reaction is stirred after 5h, after TLC detection reaction is complete.Solvent evaporated, adds after the ethyl acetate of appropriate amount, with twice of the salt acid elution (20ml * 2) of 1mol/L, twice of distilled water wash (20ml * 2), twice (20ml * 2) of saturated NaCl washing, after anhydrous sodium sulfate drying, filter, decompression is divided exactly solvent and is obtained light brown oily thing.Ethanol and water crystallization, adularescent solid is separated out, and filters to obtain crude product.After recrystallization, obtain sterling.
3) N-(3-((1H-1,2,4-triazole-5-) sulfenyl)-4-hydroxyl naphthalene-1-yl) naphthalene-2-methane amide (compound 1) is synthetic:
N-(4-hydroxyl naphthalene-1-yl)-2-naphthoamide (3.13g, 10mmol) is suspended in the CH of 200mL
2cl
2in, add NaIO
4/ SiO
2(22g, 15mmol; 0.68mmol ofNaIO
4/ 1g of SiO
2), stirring reaction 2 hours, after TLC detection reaction is complete, filters filter residue CH
2cl
2washing, filtrate decompression obtains reddish-brown solid after steaming and desolventizing.By re-crystallizing in ethyl acetate, obtain yellow solid powder (E)-N-(4-naphthalenone-1(4H) subunit)-2-naphthoamide (2.80g).
3-sulfydryl-1,2,4-triazole (2.53g, 25mmol) be dissolved in the DMF of 10ml, (E)-N-(4-naphthalenone-1(4H) subunit)-2-naphthoamide (3.11g, 10m mol) slowly join in DMF, stirring reaction 4h, after TLC detection reaction is complete, solution is poured in the distilled water of 100ml, have faint yellow solid to separate out, standing rear filtration, uses recrystallizing methanol after the filtration cakes torrefaction obtaining, obtain white solid 1.57g, overall yield: 38.17%, mp:229.1-230.3 ℃, ESI-MS m/z:413.6[M+H
+],
1h-NMR(DMSO-d6) δ 7.43(s, 1H); 7.50-7.68(m, 5H); 7.89-8.12(m, 6H); 8.29(q, J=3.2Hz, 1H); 8.54(s, 1H); 8.70(s, 1H); 10.43(s, 1H).
Method similar to Example 1, can obtain compound 2-10:
Embodiment 2 N-(3-((1H-1,2,4-triazole-5-) sulfenyl)-4-hydroxyl naphthalene-1-yl) the bromo-2-fluorobenzene of-4-sulphonamide (compound 11) is synthetic:
Compound 11
1) one-tenth of 4-amino-1-naphthols
1-nitro-naphthalene (0.86g, 5mmol) be dissolved in 13ml DMSO and be cooled to-5 ~ 5 ℃, adding KOH (1.2g, 5ml aqueous solution 20mmol), stir after 5min, drip the 2ml DMSO solution of peroxy tert-butyl alcohol t-BuOOH (1.8g, 10mmol).The about 2h of stirring at room, pours solution in 50ml 1mol/L hydrochloric acid soln after reacting completely, and separates out faint yellow solid, filters, the crude product of 1.38g of weighing after filtration cakes torrefaction to obtain.After recrystallization, obtain sterling 1.20g, faint yellow, fusing point is 166-168 ℃.
Gained 4-nitro-1-naphthols (189g, 10mmol) is dissolved in to 20ml CH
3in OH, under 10 normal atmosphere hydrogen, stirring reaction is 10 hours, the completely rear filtering palladium carbon of TLC detection reaction, and filtrate steaming removal solvent obtains 1.30g black solid powder, obtains 4-amino-1-naphthols after recrystallization, and fusing point is: 198 ℃.
2) N-(4-(4H) naphthalenone imines) the bromo-benzsulfamide of the fluoro-2-of-4-is synthetic
4-amino-1-naphthols (1.59g, 10mmol) dissolution of solid, in 20ml pyridine, adds 4-bromo-2-fluorobenzene SULPHURYL CHLORIDE (4.1g, 15mmol), and reaction is stirred after 5h; After TLC detection reaction is complete, evaporate to dryness pyridine, add 40ml ethyl acetate, twice of salt acid elution (20ml * 2) with 1mol/L, twice of distilled water wash (20ml * 2), twice (20ml * 2) of saturated NaCl washing, anhydrous sodium sulfate drying organic phase, filter, remove solvent under reduced pressure and obtain brown oil; Add 60ml dichloromethane solvent, standing 12h separates out white solid, filters to obtain crude product, and methylene dichloride recrystallization obtains pure N-(4-hydroxyl-1-naphthyl) the fluoro-benzsulfamide of the bromo-2-of-4-.
N-(4-hydroxyl-1-naphthyl) the fluoro-benzsulfamide of the bromo-2-of-4-(3.96g, 10mmol) is suspended in to the CH of 200mL
2cl
2in, add NaIO
4/ SiO
2(22g, 15mmol; 0.68mmol of NaIO
4/ 1g of SiO
2), stirring reaction 2 hours, TLC detection reaction is complete, filters filter cake CH
2cl
2washing, filtrate decompression obtains reddish-brown solid after steaming and desolventizing, re-crystallizing in ethyl acetate obtains 2.77g yellow solid powder and is N-(4-(4H) naphthalenone imines) the bromo-benzsulfamide of the fluoro-2-of-4-.
3) N-(3-((1H-1,2,4-triazole-5-) sulfenyl)-4-hydroxyl naphthalene-1-yl) the bromo-2-fluorobenzene of-4-sulphonamide (compound 11) is synthetic:
3-sulfydryl-1, 2, 4-triazole (2.53g, 25mmol) be dissolved in the DMF of 10ml, N-(4-(4H) naphthalenone imines) the bromo-benzsulfamide (3.93g of the fluoro-2-of-4-, 10mmol) divide on a small quantity and repeatedly join in DMF, stirring reaction 4h, after TLC detection reaction is complete, solution is poured in the distilled water of 100ml, there is faint yellow solid to separate out, after standing, filtration obtains using recrystallizing methanol after filter residue and drying, obtain 2.01g white solid, be N-(3-((1H-1, 2, 4-triazole-5-) sulfenyl)-4-hydroxyl naphthalene-1-yl) the bromo-2-fluorobenzene of-4-sulphonamide (compound 11), yield: 40.54%, fusing point is 232.6-234.5 ℃.ESI-MSm/z:495.35[M+H
+];
1H-NMR(DMSO-d6)；6.98(s,1H);7.40-7.53(m,4H);7.75-7.79(m,1H);7.96-7.99(m,1H);8.16-8.19(m,1H);8.60(s,1H);10.20(s,1H);10.38(s,1H);14.23(s,1H).
Method similar to Example 1, can obtain compound 11-15
Test example 1: biological test
1.[material] HUVEC, HCT116, A549, HepG2 cell strain, the blue MTT of tetramethyl-azo azoles, 10% foetal calf serum, 96 orifice plates
2.[method]
Cell cultures HUVEC, HCT116, A549, tri-kinds of tumor cell lines of HepG2 all adopt cellar culture.During test, all use logarithmic phase cell.
Growth of Cells detects (mtt assay) HUVEC, HCT116, and A549, HepG2 cell suspension is all adjusted to 1 * 105/ml, is inoculated in respectively 96 orifice plates (50 μ l/ hole), 5000 cells/well.After bed board 4h, in every hole, add 50ul to contain the substratum of different concns compound, compound final concentration in hole is respectively: 1000ug/ml, 200ug/ml, 40ug/ml, 8ug/ml, 1.6ug/ml, 0.32ug/ml, each concentration is established three multiple holes, while not adding the hole reading of cell, do blank, add the hole that cell do not add compound and make compound blank well, Sorafinib makes compound positive control.In 37 ℃, in 5% carbonic acid gas, hatch 48h, every hole adds the MTT staining fluid of 10 μ l 0.5%, continues to hatch after 4h, 2500rpm, centrifugal 30min, then abandons substratum in plate hole, adds dimethyl sulfoxide (DMSO) 200ul/ hole.In microplate reader, in 570nm place, measure the absorbancy OD value in every hole, inhibitory rate of cell growth is calculated as follows:
Inhibiting rate (%)=(the average OD value of the average OD value-experimental port of control wells) average OD value * 100% of/control wells
Table 1 cell proliferation experiment result
In table, numerical value is the mean value of three tests, the numeric representation standard deviation after " ± ".
Table I test data shows, majority of compounds demonstrates the activity suitable with positive control Sorafenib in the test of anti-tumour cell proliferative in vitro, has good DEVELOPMENT PROSPECT.
Test example 2 target compound angiogenesis inhibitor test----rat chest aorta rings (In vitro)
This test is cut into 1mm length by rat aorta and puts into Matrigel glue, and the vascular endothelial cell in aorta can be grown in Matrigel glue in the mode of sprouting, and therefore, this test is for detection of the inhibition angiogenic activity of angiogenesis inhibitor class inhibitor.
Test-compound (take compound 3 as example), Sorafenib, DMSO is dissolved to 1mM and does storage liquid
Dosage: 1,10,20 μ M
Step:
Get rat chest aorta, reject circumvascular fatty tissue, with PBS, wash multipass, with 1640 substratum, wash twice, cut aorta to 1mm, put into 96 orifice plates
Xiang Kongzhong adds Matrigel glue (BD, the article No.: 356234), 70 μ l/ holes, put in incubator of 1640 substratum 1:1 dilutions
Put after incubator 30min 1640 substratum that add 70 μ l to contain DMSO or compound; Test grouping: 12 groups of control groups, compound S orafinib group, compound; 1,10,20uM compound final concentration:; Two multiple holes of each dosage; In hole, DMSO accounts for 1/1000 of cumulative volume
Cultivate after 3 days, renew substratum, and add medicine
Cultivate and take pictures after 6 days, Sorafenib, blank, compound 3(1 μ M), compound 3(10 μ M) and compound 3(20 μ M) on the impact of rat aorta ring vasculogenesis respectively as shown in Fig. 11,2,3,4,5.Shown in result, the negative control group endotheliocyte well-grown that sprouts; Compound 3 concentration dependent under the concentration of 1-20 μ M suppresses the microvascular new life of rat artery ring.
Claims (5)
1.2-sulfo--4-amido-1-naphthol derivative, its pharmacy acceptable salt, is characterized in that: described 2-sulfo--4-amido-1-naphthol derivative is selected from following compounds:
N-(3-((1H-1,2,4-triazole-5-) sulfenyl)-4-hydroxyl naphthalene-1-yl) the bromo-2-fluorobenzene of-4-sulphonamide;
N-(3-((7H-purine-6-) sulfenyl)-4-hydroxyl naphthalene-1-yl)-3,4-dimethoxy benzsulfamide;
N-(3-((7H-purine-6-) sulfenyl)-4-hydroxyl-6,7-dimethoxy-naphthalene-1-yl)-3,4-dimethoxy benzsulfamide
N-(3-((7H-purine-6-) sulfenyl)-4-hydroxyl-6,7-dimethoxy-naphthalene-1-yl)-2,6-dichlorobenzene sulphonamide.
2. the method for preparation 2-sulfo--4-amido-1-naphthol derivative claimed in claim 1, is characterized in that: comprise the steps:
1) with R
2, R
3the 1-nitro-naphthalene replacing is raw material, take DMSO and water as mixed solvent, react the contraposition introducing hydroxyl at nitro under potassium hydroxide exists with peroxy tert-butyl alcohol, then with palladium carbon, makes catalyzer hydro-reduction and obtain intermediate (II);
2) by intermediate (II) and R
1the SULPHURYL CHLORIDE replacing is at room temperature reacted 8-12 hour, obtains key intermediate (III), then obtains quinoid intermediate (IV) through sodium periodate oxidation;
3) by quinoid intermediate (IV) and R
4there is Michael reaction and obtain ultimate aim product in SH:
Wherein,
L is linking group, Xuan Zi – SO
2-;
R
1be selected from phenyl, described phenyl can optionally be replaced by one or more following groups: methoxyl group or halogen;
R
2be selected from hydrogen or methoxyl group;
R
3be selected from hydrogen or methoxyl group;
R
4be selected from and replace or unsubstituted 7H-purine-6-base.
3. a pharmaceutical composition, it comprises 2-sulfo--4-amido-1-naphthol derivative claimed in claim 1, its pharmacy acceptable salt, and pharmaceutically acceptable auxiliary material.
4. 2-sulfo--4-amido-1-naphthol derivative claimed in claim 1, the purposes of its pharmacy acceptable salt in preparing tyrosine kinase inhibitor.
5. 2-sulfo--4-amido-1-naphthol derivative claimed in claim 1, its pharmacy acceptable salt purposes in the medicine of the tumor cell proliferation for the preparation of driving with receptor tyrosine kinase in treating and/or preventing Mammals and migration.
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| CN109846840B (en) * | 2018-12-18 | 2021-08-10 | 江西润泽药业有限公司 | Solid dosage form of vascular endothelial growth factor inhibitor and preparation method thereof |
| CN109651294B (en) * | 2018-12-18 | 2021-07-06 | 江西润泽药业有限公司 | 1, 4-diaminenaphthalene derivative and preparation method and application thereof |
| CN110437082A (en) * | 2019-08-28 | 2019-11-12 | 哈尔滨工业大学 | A kind of heteroaromatic compounds 2,4,6,8- tetramino -1,5- naphthalenediol hydrochloride and its synthetic method |
| CN115894317A (en) * | 2021-09-22 | 2023-04-04 | 杭州天玑济世生物科技有限公司 | Micromolecular compound with naphthylthiophenol ether structure and application thereof |
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| Jie Qin et al..Identification of a Novel Family of BRAFV600E Inhibitors.《Journal of Medicinal Chemistry》.2012,第55卷第5220-5230页. * |
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