CN104177288A - Selenosemicarbazone derivative, and pharmaceutical composition and application thereof - Google Patents
Selenosemicarbazone derivative, and pharmaceutical composition and application thereof Download PDFInfo
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- CN104177288A CN104177288A CN201310194130.9A CN201310194130A CN104177288A CN 104177288 A CN104177288 A CN 104177288A CN 201310194130 A CN201310194130 A CN 201310194130A CN 104177288 A CN104177288 A CN 104177288A
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- selenourea
- independently selected
- pyridine
- phenyl
- base
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/53—Nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Abstract
The invention relates to a selenosemicarbazone derivative, and a pharmaceutical composition and an application thereof. Specifically, the invention relates to a compound shown as a formula I or an isomer thereof, a pharmaceutically acceptable salt, a composition comprising the compound shown as the general formula I or the isomer thereof, the pharmaceutically acceptable salt and a pharmaceutically acceptable vector, and applications of the compound shown as the general formula I or the isomer thereof and the pharmaceutically acceptable salt in preparing drugs for resisting tumor or treating diseases or symptoms related to the tumor. The formula I is shown in the description.
Description
Technical field
The present invention relates to Selenosemicarbazones derivative, this compounds has the activity of significant anti-tumour cell proliferative and inducing apoptosis of tumour cell, the tumour cell of resistance is had active very significantly.The invention still further relates to method, the pharmaceutical composition that comprises this Selenosemicarbazones derivative and this Selenosemicarbazones derivative of this Selenosemicarbazones derivative of preparation as antitumor drug or for anti-tumor application.
Background technology
Tumour is normal cell that growing in human body or ripe, under the long term of some undesirable element, and the cell mass of certain portion, the hyperplasia of appearance or abnormal differentiation and the true tumor that generates forms lump in part.But it is different with cell from normal tissue, not according to Normocellular metabolic rule growth, and become unfettered and control, cause cell to present abnormal form, function and metabolism, so that can destroy the structure of normal histoorgan and affect its function.Malignant cell can also infiltrate and spread towards periphery, and even diffusion transfer, to other organ-tissues, continues hyperplasia at double, causes human body or life are threatened greatly.
Cancer is the disease that the mankind are difficult to capture always, and current embolic chemotherapy is still not remarkable for the result for the treatment of of many cancers.The antitumor drug that development of new has highly selective is very necessary.Maintaining with cell proliferation of cytoactive all needs iron, the metallic elements such as copper, these elements, as the cofactor of many enzymes or albumen, participate in the links in vital movement and go, the effect important to maintaining of cell life, has great significance to maintaining of human life.
In cancer therapy at present, many curative effect of medication are not ideal enough, produce the problems such as resistance, still Structure of need novelty, can produce by number of mechanisms the compound of antitumor action, these compounds have the activity of significant anti-tumour cell proliferative and inducing apoptosis of tumour cell, the tumour cell of resistance is had to activity very significantly, for the treatment of tumour provides new medicine and strategy.
Summary of the invention
Inventor design and synthesized the new Selenosemicarbazones derivative of a class, it is the compound (being below sometimes also referred to as " compound of the present invention ") of formula I, II, III, IV and V, they have good anti-tumor activity, can be used for the treatment of kinds of tumors, comprise the cancer of leukemia, glioblastoma, lymphoma, melanoma and people liver, bone, skin, brain, pancreas, lung, breast, stomach, colon, rectum, prostate gland, ovary and uterine neck.
On the one hand, the invention provides the compound of following formula I,
Or its isomer, pharmacy acceptable salt, solvate or N-oxide compound, wherein
R
1and R
2independently selected from aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic radical or heterocyclic radical alkyl; And
R
3and R
4independently selected from hydrogen, hydroxyl, halogen, amino, nitro, trifluoromethyl, C
1-C
10alkyl, C
2-C
l0thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl, C
3-C
10cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic radical or heterocyclic radical alkyl;
Each alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclic radical part in above-mentioned group are optionally replaced by one or more substituting groups, and this substituting group is independently selected from hydroxyl, halogen, amino, nitro, trifluoromethyl ,-OR
5,-C (O) R
5,-C (O) OR
5,-NR
5c (O) OR
6,-OC (O) R
5,-NR
5sO
2r
6,-SO
2nR
5r
6,-NR
5c (O) R
6,-C (O) NR
5r
6,-NR
5c (O) NR
6r
7,-NR
5r
6, C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl, C
3-C
10cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic radical or heterocyclic radical alkyl,
Wherein, R
5, R
6and R
7independently selected from hydroxyl, halogen, amino, nitro, trifluoromethyl, C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl or C
3-C
10cycloalkyl.
In one embodiment, the invention provides the compound shown in formula II,
Or its isomer, pharmacy acceptable salt, solvate or N-oxide compound, wherein
X
1, X
2, X
3and X
4independently selected from C or N;
R
3and R
4independently selected from hydrogen, hydroxyl, halogen, amino, nitro, trifluoromethyl, C
1-C
10alkyl, C
2-C
l0thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl, C
3-C
10cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic radical or heterocyclic radical alkyl; And
R
8and R
9independently selected from hydrogen, hydroxyl, halogen, amino, nitro, trifluoromethyl ,-NR
5c (O) OR
6,-OC (O) R
5,-NR
5sO
2r
6,-SO
2nR
5r
6,-NR
5c (O) R
6,-C (O) NR
5r
6, NR
5c (O) NR
6r
7, NR
5r
6, C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl, C
3-C
10cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic radical or heterocyclic radical alkyl;
Wherein, R
5, R
6and R
7independently selected from hydroxyl, halogen, amino, nitro, trifluoromethyl, C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl or C
3-C
10cycloalkyl.
In another embodiment, the invention provides the compound shown in formula II,
Or its isomer, pharmacy acceptable salt, solvate or N-oxide compound, wherein
X
1, X
2, X
3and X
4independently selected from C or N;
R
3and R
4independently selected from hydrogen, hydroxyl, halogen, amino, nitro, trifluoromethyl, C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl, C
6-C
10aryl or there is the heteroaryl of 5～10 atoms, this heteroaryl has at least one heteroatoms independently selected from N, O or S, wherein said alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl or heteroaryl are optionally replaced by one or more substituting groups, and this substituting group is independently selected from hydroxyl, halogen, amino, nitro, trifluoromethyl, C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl or C
3-C
10cycloalkyl; And
R
8and R
9independently selected from hydrogen, hydroxyl, halogen, amino, nitro, trifluoromethyl, C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl or C
3-C
10cycloalkyl.
In a further embodiment, the invention provides the compound shown in formula II,
Or its isomer, pharmacy acceptable salt, solvate or N-oxide compound, wherein
X
1, X
2, X
3and X
4independently selected from C or N;
R
3and R
4independently selected from hydrogen, hydroxyl, halogen, amino, nitro, trifluoromethyl, C
1-C
6alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
3-C
8cycloalkyl, phenyl or there is the heteroaryl of 5～7 atoms, this heteroaryl has at least one heteroatoms independently selected from N, O or S; And
R
8and R
9be hydrogen independently.
In a further embodiment, the invention provides the compound shown in formula III,
Or its isomer, pharmacy acceptable salt, solvate or N-oxide compound, wherein
X
1, X
2, X
3and X
4independently selected from C or N;
R
3and R
4independently selected from hydrogen, hydroxyl, halogen, amino, nitro, trifluoromethyl, C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl, C
6-C
10aryl or there is the heteroaryl of 5～10 atoms, this heteroaryl has at least one heteroatoms independently selected from N, O or S, wherein said alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl or heteroaryl are optionally replaced by one or more substituting groups, and this substituting group is independently selected from hydroxyl, halogen, amino, nitro, trifluoromethyl, C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl or C
3-C
10cycloalkyl; And
R
8and R
9independently selected from hydrogen, hydroxyl, halogen, amino, nitro, trifluoromethyl, C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl or C
3-C
10cycloalkyl.
In a further embodiment, the invention provides the compound shown in formula IV,
Or its isomer, pharmacy acceptable salt, solvate or N-oxide compound, wherein
X
1, X
2, X
3and X
4independently selected from C or N;
R
3and R
4independently selected from hydrogen, hydroxyl, halogen, amino, nitro, trifluoromethyl, C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl, C
6-C
10aryl or there is the heteroaryl of 5～10 atoms, this heteroaryl has at least one heteroatoms independently selected from N, O or S, wherein said alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl or heteroaryl are optionally replaced by one or more substituting groups, and this substituting group is independently selected from hydroxyl, halogen, amino, nitro, trifluoromethyl, C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl or C
3-C
10cycloalkyl; And
R
8and R
9independently selected from hydrogen, hydroxyl, halogen, amino, nitro, trifluoromethyl, C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl or C
3-C
10cycloalkyl.
In a further embodiment, the invention provides the compound shown in formula V,
Or its isomer, pharmacy acceptable salt, solvate or N-oxide compound, wherein
X
1, X
2, X
3and X
4independently selected from C or N; And
R
3and R
4independently selected from hydrogen, hydroxyl, halogen, amino, nitro, trifluoromethyl, C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl, C
6-C
10aryl or there is the heteroaryl of 5～10 atoms, this heteroaryl has at least one heteroatoms independently selected from N, O or S, wherein said alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl or heteroaryl are optionally replaced by one or more substituting groups, and this substituting group is independently selected from hydroxyl, halogen, amino, nitro, trifluoromethyl, C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl or C
3-C
10cycloalkyl.
In a further embodiment, the invention provides the compound shown in formula V,
Or its isomer, pharmacy acceptable salt, solvate or N-oxide compound, wherein
X
1, X
2, X
3and X
4independently selected from C or N; And
R
3and R
4independently selected from hydrogen, hydroxyl, halogen, amino, nitro, trifluoromethyl, C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl, phenyl or have the heteroaryl of 5～7 atoms, this heteroaryl has at least one heteroatoms independently selected from N, O or S.
In a further embodiment, the invention provides the compound shown in formula V,
Or its isomer, pharmacy acceptable salt, solvate or N-oxide compound, wherein
X
1, X
2, X
3and X
4independently selected from C or N; And
R
3and R
4independently selected from hydrogen, hydroxyl, halogen, amino, nitro, trifluoromethyl, C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl, phenyl or pyridyl.
In a further embodiment, the invention provides the compound shown in formula V,
Or its isomer, pharmacy acceptable salt, solvate or N-oxide compound, wherein
X
1, X
2, X
3and X
4independently selected from C or N; And
R
3and R
4independently selected from hydrogen, hydroxyl, halogen, amino, nitro, trifluoromethyl, C
1-C
6alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
3-C
8cycloalkyl, phenyl or pyridyl.
In a further embodiment, the invention provides the compound shown in formula V,
Or its isomer, pharmacy acceptable salt, solvate or N-oxide compound, wherein
X
1, X
2, X
3and X
4independently selected from C or N; And
R
3and R
4independently selected from hydrogen, amino, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, vinyl, allyl group, propenyl, butenyl, alkene butyl, phenyl or pyridyl.
In a specific embodiment, the invention provides compound, this compound is selected from lower group of compound:
2-bis-(pyridine-2 base) methene amido-selenourea
N-methyl-2-bis-(pyridine-2 base) methene amido-selenourea
N-ethyl-2-bis-(pyridine-2 base) methene amido-selenourea
N-allyl group-2-bis-(pyridine-2 base) methene amido-selenourea
N-phenyl-2-bis-(pyridine-2 base) methene amido-selenourea
N-cyclopropyl-2-bis-(pyridine-2 base) methene amido-selenourea
N-cyclohexyl-2-bis-(pyridine-2 base) methene amido-selenourea
N, N-dimethyl-2-bis-(pyridine-2 base) methene amido-selenourea
N-(pyridine-2 base)-2-bis-(pyridine-2 base) methene amido-selenourea
N-cyclopentyl-2-bis-(pyridine-2 base) methene amido-selenourea
N-cyclopropyl-2-(phenyl (pyridine-2-yl)) methene amido-selenourea
N-methyl-2-(phenyl (pyridine-2-yl)) methene amido-selenourea
N-allyl group-2-(phenyl (pyridine-2-yl)) methene amido-selenourea
N-sec.-propyl-2-(phenyl (pyridine-2-yl)) methene amido-selenourea
N-sec.-propyl-2-bis-(pyridine-2 base) methene amido-selenourea
N-butyl-2-bis-(pyridine-2 base) methene amido-selenourea
N-cyclohexyl-2-(phenyl (pyridine-2-yl)) methene amido-selenourea
N-ethyl-2-(phenyl (pyridine-2-yl)) methene amido-selenourea
N-propyl group-2-bis-(pyridine-2 base) methene amido-selenourea
N-propyl group-2-(phenyl (pyridine-2-yl)) methene amido-selenourea
N-cyclopentyl-2-(phenyl (pyridine-2-yl)) methene amido-selenourea
N-cyclopentyl-2-(phenyl (pyrimidine-2-base)) methene amido-selenourea
N-propyl group-2-(phenyl (pyrimidine-2-base)) methylamino-selenourea
N-ethyl-2-(phenyl (pyrimidine-2-base)) methene amido-selenourea
N-cyclohexyl-2-(phenyl (pyrimidine-2-base)) methene amido-selenourea
N-allyl group-2-(phenyl (pyrimidine-2-base)) methylene amino-selenourea
N-sec.-propyl-2-(phenyl (pyrimidine-2-base)) methene amido-selenourea
N-methyl-2-(phenyl (pyrimidine-2-base)) methene amido-selenourea
N-butyl-2-(phenyl (pyrimidine-2-base)) methene amido-selenourea and N-cyclopropyl-2-(phenyl (pyrimidine-2-base)) methene amido-selenourea,
Or their isomer, pharmacy acceptable salt, solvate or N-oxide compound.
On the other hand, the invention provides a kind of method of preparing the compounds of this invention, it comprises the steps:
Make substituted-amino thiocarbamide and methyl iodide heating reflux reaction in ethanolic soln, obtain first thiosemicarbazide, then under nitrogen protection, react with the fresh sodium hydrogen selenide making at room temperature replace selenosemicarbazide
Again on the one hand, the invention provides a kind of for antitumor medicine composition, the compound that it comprises above-mentioned formula I, II, III, IV or V, or their isomer, pharmacy acceptable salt, solvate or N-oxide compound, and at least one pharmaceutically acceptable carrier.
Again on the one hand, the invention provides a kind of pharmaceutical composition, the compound that it comprises above-mentioned formula I, II, III, IV or V, or their isomer, pharmacy acceptable salt, solvate or N-oxide compound, comprise in addition one or more other antitumor drugs, for example replace Buddhist nun's series antineoplastic medicament, and at least one pharmaceutically acceptable carrier.
Again on the one hand, the invention provides the compound of above-mentioned formula I, II, III, IV or V, or their isomer, pharmacy acceptable salt, solvate or N-oxide compound, they are used as anti-tumor drug, or are used for the treatment of the especially mankind's tumour of experimenter.
Again on the one hand, the invention provides a kind of especially method of the mankind's tumour of experimenter for the treatment of, it comprises the compound for the treatment of above-mentioned formula I, II, III, IV or the V of significant quantity to this experimenter, or their isomer, pharmacy acceptable salt, solvate or N-oxide compound, and optionally combine and give one or more other antitumor drugs, for example, for Buddhist nun's series antineoplastic medicament.
Again on the one hand, the invention provides the compound of above-mentioned formula I, II, III, IV or V or their isomer, pharmacy acceptable salt, solvate or N-oxide compound in the purposes of preparing in medicine, wherein said medicine is used for the treatment of the especially mankind's tumour of experimenter.
Now as follows for describing term definition of the present invention by what occur in present specification and claims.For specific term, if the implication that the implication defining in the application and those skilled in the art understand is conventionally inconsistent, be as the criterion with the implication defining in the application; If do not defined in this application, it has the implication that those skilled in the art understand conventionally.
The term " alkyl " using in the present invention refers to straight or branched univalent saturated hydrocarbon radical." C
1-C
10alkyl " refer to the straight or branched alkyl with 1～10 carbon atom, such as methyl, ethyl, propyl group, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, amyl group, 2-amyl group, isopentyl, neo-pentyl, hexyl, 2-hexyl, 3-hexyl, 3-methyl amyl, heptyl and octyl group etc.Term " C
1-C
6alkyl " mean to have 1～6, the straight or branched alkyl of 1,2,3,4,5 or 6 carbon atom, typically is methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, amyl group and hexyl etc.Similarly, term " C
1-C
3alkyl " mean to have the straight or branched alkyl of 1,2 or 3 carbon atom, i.e. methyl, ethyl, n-propyl and sec.-propyl.Preferably C of alkyl in the present invention
1-C
6alkyl, is more preferably C
1-C
3alkyl.
Term " the C using in the present invention
2-C
10thiazolinyl " refer to the alkyl with the two keys of 2～10 carbon atoms and at least one.Similarly, term " C
2-C
6thiazolinyl " refer to have 2～6, i.e. the alkyl of 2,3,4,5 or 6 carbon atoms and at least one two key, its include but not limited to vinyl, propenyl, 1-fourth-3-thiazolinyl, 1-penta-3-thiazolinyl and 1-oneself-5-thiazolinyl etc.In the present invention, preferably there is 3-5, i.e. the thiazolinyl of 3,4 or 5 carbon atoms.
Term " the C using in the present invention
2-C
10alkynyl " refer to the alkyl with 2～10 carbon atoms and at least one three key.Similarly, term " C
2-C
6alkynyl " refer to have 2～6, i.e. the alkyl of 2,3,4,5 or 6 carbon atoms and at least one three key, it includes but not limited to ethynyl, proyl, butynyl, pentyne-2-base etc.In the present invention, preferably have 3～5, i.e. the alkynyl of 3,4 or 5 carbon atoms.
The term " halogen " using in the present invention refers to fluorine, chlorine, bromine and iodine atom.
The term " aryl " using in the present invention refers to the optional substituted monocycle or the bicyclic hydrocarbon loop systems that comprise at least one unsaturated aromatic ring, preferably has 6～10, i.e. the aryl of 6,7,8,9 or 10 carbon atoms.The example of the aryl in the present invention comprises phenyl, naphthyl, 1,2,3,4-tetralyl, indyl and indenyl etc.Aryl in the present invention can be replaced by following group: C
1-C
6alkyl, C
1-C
6alkoxyl group, itrile group, halogen, hydroxyl, amino, nitro, list (C
1-C
6) alkylamino, two (C
1-C
6) alkylamino, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
1-C
6haloalkyl or C
1-C
6halogenated alkoxy.
The term " heteroaryl " using in the present invention refers to and comprises at least one heteroatomic optional substituted monocycle independently selected from N, O or S or the unsaturated aromatic ring system of dicyclo, preferably has 5～10, i.e. the heteroaryl of 5,6,7,8,9 or 10 atoms.The example of " heteroaryl " include but not limited to thienyl, pyridyl, thiazolyl, isothiazolyl, furyl, pyrryl, triazolyl, imidazolyl, triazinyl,
di azoly,
azoles base, different
azoles base, pyrazolyl, imidazoles ketone group,
azoles, thiazole ketone group, tetrazyl, thiadiazolyl group, benzimidazolyl-, benzo
azoles base, benzothiazolyl, tetrahydrochysene Triazolopyridine base, tetrahydrochysene triazolopyrimidinyl, benzofuryl, benzothienyl, thianaphthenyl, indyl, pseudoindoyl, pyriconyl, pyridazinyl, pyrazinyl, pyrimidyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolyl, imidazopyridyl,
azoles pyridyl, thiazole pyridyl, Imidazopyridazine base,
azoles pyridazinyl, thiazole pyridazinyl, pteridyl, furazan base, benzotriazole base, Pyrazolopyridine base and purine radicals etc.Heteroaryl in the present invention can be replaced by following group: C
1-C
6alkyl, C
1-C
6alkoxyl group, itrile group, halogen, hydroxyl, amino, nitro, list (C
1-C
6) alkylamino, two (C
1-C
6) alkylamino, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
1-C
6haloalkyl or C
1-C
6halogenated alkoxy.
Term " the C using in the present invention
3-C
10cycloalkyl " refer to have 3～10, i.e. the saturated carbon ring group of 3,4,5,6,7,8,9 or 10 carbon atoms.This cycloalkyl can be that monocycle or many rings condense system, and can condense on aromatic ring.The example of these groups comprises cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl etc.Cycloalkyl herein can be unsubstituted, or is replaced by suitable group in one or more commutable positions.For example, the cycloalkyl in the present invention can optionally be replaced by following group: C
1-C
6alkyl, C
1-C
6alkoxyl group, itrile group, halogen, hydroxyl, amino, nitro, list (C
1-C
6) alkylamino, two (C
1-C
6) alkylamino, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
1-C
6haloalkyl or C
1-C
6halogenated alkoxy.
The term " heterocyclic radical " using in the present invention refers to and comprises at least one and maximum four heteroatomic optional substituted monocycles independently selected from N, O or S and dicyclo is saturated, fractional saturation or undersaturated ring system, preferably have 4～10, i.e. 5,6 or 7 of 4,5,6,7,8,9 or 10 atoms yuan of heterocyclic radicals, condition is that the ring of this heterocyclic radical does not contain two adjacent O or S atom.Preferred heterocyclic radical includes but not limited to pyrrolidyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, piperidyl, morpholinyl or piperazinyl etc.Heterocyclic radical in the present invention can be replaced by following group: C
1-C
6alkyl, C
1-C
6alkoxyl group, itrile group, halogen, hydroxyl, amino, nitro, list (C
1-C
6) alkylamino, two (C
1-C
6) alkylamino, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
1-C
6haloalkyl or C
1-C
6halogenated alkoxy.
The term " arylalkyl " using in the present invention refers to the alkyl as defined above being replaced by one or more aryl as defined above.Preferred arylalkyl is aryl-C
l-C
3alkyl.The example of the arylalkyl in the present invention comprises benzyl and phenylethyl etc.
The term " heteroarylalkyl " using in the present invention refers to the alkyl as defined above by heteroaryl replaces as defined above.Preferred heteroarylalkyl is 5-or the heteroaryl-C of 6-unit
1-C
3-alkyl.The example of the heteroarylalkyl in the present invention comprises pyridyl ethyl etc.
The term " heterocyclic radical alkyl " using in the present invention refers to the alkyl as defined above by heterocyclic radical replaces as defined above.Preferred heterocyclic radical alkyl is 5 or 6 yuan of heterocyclic radical-C
l-C
3-alkyl.The example of the heterocyclic radical alkyl in the present invention comprises tetrahydropyrans ylmethyl.
Term " the C using in the present invention
3-C
10cycloalkylalkyl " refer to by C as defined above
3-C
10the alkyl as defined above of cycloalkyl substituted.C in the present invention
3-C
10cycloalkylalkyl is 5 or 6 yuan of cycloalkyl-C preferably
l-C
3-alkyl.
The term " pharmacy acceptable salt " using in the present invention means acceptable in pharmacy and has the salt of the compounds of this invention of the required pharmacological activity of parent compound.This class salt comprises: the salt of sour addition forming with mineral acid or with organic acid, all example hydrochloric acids of described mineral acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc.; Described organic acid is such as acetic acid, propionic acid, caproic acid, cyclopentyl propionic acid, oxyacetic acid, pyruvic acid, lactic acid, propanedioic acid, succsinic acid, oxysuccinic acid, toxilic acid, fumaric acid, tartrate, citric acid, phenylformic acid, styracin, amygdalic acid, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, naphthene sulfonic acid, camphorsulfonic acid, glucoheptonic acid, glyconic acid, L-glutamic acid, hydroxynaphthoic acid, Whitfield's ointment, stearic acid, muconic acid etc.; Or the acid proton existing on parent compound is by metal ion, the salt for example, forming when alkalimetal ion or alkaline-earth metal ions replace; Or the coordination compound forming with organic bases, described organic bases is such as thanomin, diethanolamine, trolamine, N-METHYL-ALPHA-L-GLUCOSAMINE etc.
The term " solvate " using in the present invention mean the compounds of this invention acceptable solvent in pharmacy be combined form material.In pharmacy, acceptable solvent comprises water, ethanol, acetic acid etc.Solvate comprises the solvate of stoichiometric quantity and the solvate of calculated amount non-chemically, is preferably hydrate.Compound of the present invention can water or various organic solvent crystallization or recrystallization, in this case, may form all kinds of SOLVENTS compound.
The term " experimenter " using in the present invention comprises Mammals and people, is preferably people.
The term " treatment significant quantity " using in the present invention means the consumption of the compounds of this invention, this amount when having experimenter's administration that this treatment needs be enough to institute for the patient's condition produce the effect for the treatment of.This treatment significant quantity can be according to compound, disease and seriousness thereof and the experimenter's that treats age, body weight etc. and changing." treatment " in this term mean in described experimenter to eliminate or reduce be treated tumour tumour cell, reduce to be treated the size of tumour or prevent its shift and improve or eliminate for one or more symptoms of tumor disease.
Those skilled in the art will appreciate that compound of the present invention exists steric isomerism, for example, exist cis-trans-isomer.Therefore, in this specification sheets, in the time mentioning compound of the present invention, the compounds of this invention comprises compound and pharmacy acceptable salt, steric isomer, solvate and the N-oxide compound of arbitrary formula in described formula I～V.Compound of the present invention also comprises the active metabolite of the compounds of this invention in mammalian body.
The synthetic schemes of the compounds of this invention is as follows:
Wherein, R
1be selected from hydrogen, C
1-C
10alkyl, C
2-C
l0thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl, C
3-C
10cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic radical or heterocyclic radical alkyl.
Can prepare the compounds of this invention by the either method showing in following synthetic schemes:
Method one:
Method two:
The product of reaction can adopt the standard technique in this area to separate and purifying, such as extraction, chromatography, crystallization and distillation etc.
" embodiment " part of this specification sheets for example understands the preparation method of the compounds of this invention and the effect of antitumor cell thereof.
Pharmaceutical composition of the present invention comprises formula formula I compound of the present invention or its isomer, pharmacy acceptable salt or hydrate and one or more suitable pharmaceutically acceptable carriers of effective dose.The pharmaceutical carrier here includes but not limited to: ion-exchanger, aluminum oxide, aluminum stearate, Yelkin TTS, serum protein is as human serum albumin, and buffer substance is as phosphoric acid salt, glycerine, Sorbic Acid, potassium sorbate, the partial glycerol ester mixture of saturated vegetable fatty acid, water, salt or ionogen, as protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt, colloided silica, Magnesium Trisilicate, polyvinylpyrrolidone, cellulosic material, polyoxyethylene glycol, Xylo-Mucine, polyacrylic ester, beeswax, lanolin.
The pharmaceutical composition of the compounds of this invention can be used with any-mode below: oral, spraying sucks, rectal application, nasal cavity applied medicine, cheek medication, local application, non-enterally administer, as subcutaneous, vein, intramuscular, intraperitoneal, in sheath, in ventricle, in breastbone and intracranial injection or input, or by the medication of a kind of outer planting reservoir.Wherein preferred oral, intraperitoneal or intravenous administration mode.
In the time of oral medication, the compounds of this invention can be made into oral acceptable dosage form arbitrarily, includes but not limited to tablet, capsule, the aqueous solution or aqeous suspension.Wherein, the carrier that tablet uses generally comprises lactose and W-Gum, also can add in addition lubricant as Magnesium Stearate.The thinner that capsule preparations uses generally comprises lactose and dried corn starch.Aqueous suspension preparation normally mixes use by activeconstituents with suitable emulsifying agent and suspension agent.If need, also can add some sweeting agents, perfume compound or tinting material in above oral preparations form.
In the time of local application, particularly treat local external application easy to reach and suffer from face or organ, during as eyes, skin or lower intestinal tract nervous system disease, can the compounds of this invention be made to different local application's dosage forms according to different trouble faces or organ, be described as follows:
In the time of eye topical application, the compounds of this invention can be mixed with the dosage form of a kind of micronization suspension or solution, the carrier that uses for waiting Sterile Saline of the certain pH of oozing, wherein can add also not adding preservative agent as zephiran chloride alkoxide.For eye use, also compound can be made to paste form as vaseline paste.
In the time of topical application, the compounds of this invention can be made into suitable ointment, lotion or creme dosage form, wherein activeconstituents is suspended or is dissolved in one or more carriers.The spendable carrier of ointment formulation includes but not limited to: mineral oil, Albolene, white vaseline, propylene glycol, polyoxyethylene, polyoxytrimethylene, emulsifying wax and water; The spendable carrier of lotion or creme includes but not limited to: mineral oil, and sorbitan monostearate, polysorbate60, n-Hexadecane ester type waxes, cetene is fragrant and mellow, 2-Standamul G, benzyl alcohol and water.
The all right aseptic injection preparation form medication of the compounds of this invention, comprises aseptic injection water or oil suspension or aseptic injectable solution.Wherein, spendable carrier and solvent comprise water, Ringer's solution and isotonic sodium chlorrde solution.In addition, the fixed oil of sterilizing also can
As solvent or suspension medium, as direactive glyceride or two glyceryl ester.
The amount of the compounds of this invention that experimenter is given depends on the type of described disease or the patient's condition and severity and experimenter's feature, as general health situation, age, sex, body weight and the tolerance level to medicine, also depend on the type of preparation and the administering mode of medicine, and the factor such as administration cycle or timed interval.Those skilled in the art can determine suitable dosage according to these factors and other factors.Generally speaking, the per daily dose that compound of the present invention is used for the treatment of tumour can be about 1～2000 milligram, and this per daily dose can optionally once or several times give.The compounds of this invention can provide in dose unit, and the content in dose unit can be 0.1～200 milligram, for example 1～100 milligram.
The experiment proved that, compound of the present invention all has restraining effect very significantly to the survival rate of 6 kinds of different tumour cells, particularly the effect of the tumour cell to resistance is obviously better than existing clinical treatment medicine lapatinibditosylate (lapatinib), and effect has greatly improved.After compound of the present invention and lapatinibditosylate combined utilization, there is synergism significantly.Compound of the present invention represents good application prospect with existing for Buddhist nun's class drug combination clinically.
Therefore, compound of the present invention can be used for the treatment of kinds of tumors, for example, be used for the treatment of the cancer of leukemia, glioblastoma, lymphoma, melanoma and people liver, bone, skin, brain, pancreas, lung, breast, stomach, colon, rectum, prostate gland, ovary and uterine neck.Particularly advantageously, compound of the present invention and other antitumor drug coupling can produce the useful unforeseeable result for the treatment of of making us.Experimental result shows, compound of the present invention when as the antitumor drug coupling of protein tyrosine kinase inhibitors, the effect that can produce collaborative treatment tumour.The described antitumor drug as protein tyrosine kinase inhibitors comprises for Buddhist nun's series antineoplastic medicament, specifically includes but not limited to imatinib (Inatinib), Gefitinib (Gefinib), erlotinib (Erlotnib), Sutent (Sunitinib), Dasatinib (Dasatinib) and lapatinibditosylate (Lapatinib).
Embodiment
The following examples are the preferred illustrative preferred versions of the present invention, and the present invention is not constituted any limitation.
Melting point compound is measured by RY-1 type melting point apparatus, and temperature is not calibrated.
1h NMR spectrum is measured by Bruker ARX400 type nuclear magnetic resonance spectrometer.
Embodiment 1:N-methyl-2-bis-(pyridine-2 base) methene amido-selenourea
Step 1.S-methyl sulfo-4-methyl-3-thiosemicarbazide
In 50 milliliters of single port bottles, add 0.423g (4mmol) 4-methyl-3-thiosemicarbazide, 10ml dehydrated alcohol and 0.568g(4mmol) methyl iodide, 85 DEG C of back flow reaction one hour, obtain the ethanolic soln of S-methyl sulfo-4-methyl-3-thiosemicarbazide, cooling, there is solid to separate out, be spin-dried for solvent, obtain S-methyl sulfo-4-methyl-3-thiosemicarbazide solid (0.43g, 90%).
Step 2.4-methyl-3-selenosemicarbazide
Toward new ready-made selenium hydracid sodium 0.41g(4mmol) add sodium carbonate 0.42g(4mmol in ethanol (10ml) solution), S-methyl sulfo-4-methyl-3-thiosemicarbazide 0.54g (4mmol) solid is joined in selenium hydracid sodium ethoxide solution, room temperature reaction 20h, generate 4-methyl-3-selenosemicarbazide (0.49g, 80%).
React complete, in reaction solution, add 2ml glacial acetic acid, logical nitrogen flooding is driven the Selenium hydride methyl mercaptan gas of generation out of simultaneously, adds device for absorbing tail gas (2% plumbic acetate solution 400ml), and the time, 30～60min. was disposed.
1H-NMR（400MHz，DMSO）δppm：2.953～2.962（d，3H），4.455（m，2H），8.123（m，1H），9.020（m，1H）。
Step 3.N-methyl-2-bis-(pyridine-2 base) methene amido-selenourea
Take 0.558g(3mmol) two (2-pyridine) ketone, be dissolved in 5ml dehydrated alcohol, then add 4-methyl-3-selenosemicarbazide 0.46g (3mmol), stir, ice acetic acid 1ml, reflux 2～3h. is after completion of the reaction, filtered while hot, filtrate has solid to separate out, and is spin-dried for partial solvent, refilters, use washing with alcohol solid, recrystallization, finally obtains yellow solid (0.64g, 66.7%).
1H-NMR（400MHz，DMSO）δppm：3.136～3.147（d，3H），7.469～7.511（m，1H）7.527～7.529（d，1H），7.531～7.620（m，1H），7.969～7.974（m，1H）8.000～8.005（m，1H），8.241～8.264（d，1H），8.578～8.590（d，1H），8.828～8.840（d，1H）9.259～9.270（d，1H），13.568（s，1H）。HLPC-MS?m/z：320.2[M+1]
+。
Embodiment 2:2-bis-(pyridine-2 base) methene amido-selenourea
Method is with embodiment 1, intermediate selenosemicarbazide,
1h-NMR(400MHz, DMSO) δ ppm:4.521(s, 2H), 7.644(m, 1H) and, 7.985(m, 1H), 9.082(d, 1H) and, product yellow solid 2-bis-(pyridine-2 base) methene amido-selenourea
1h-NMR(400MHz, DMSO) δ ppm:7.477～7.495(m, 1H), 7.523～7.543(d, 1H), 7.606～7.625(m, 1H), 7.933～7.957(m, 1H), 7.990～8.013(m, 1H), 8.324～8.345(d, 1H), 8.562～8.572(d, 1H), 8.828～8.839(d, 1H) 8.921(d, 1H) 9.272(d, 1H), 13.275(s, 1H), HLPC-MS m/z:306.1[M+1]
+.
Embodiment 3:N-allyl group-2-bis-(pyridine-2 base) methene amido-selenourea
Method is with embodiment 1, intermediate 4-allyl group-3-selenosemicarbazide
1h-NMR(400MHz, DMSO) δ ppm:4.139(m, 2H), 4.529(m, 2H), 5.074～5.142(m, 2H), 5.829～5.872(m, 1H), 8.208(m, 1H), 9.150(m, 1H), product yellow solid N-allyl group-2-bis-(pyridine-2 base) methene amido-selenourea
1h-NMR(400MHz, DMSO) δ ppm:4.3296～4.3584(m, 2H), 5.1507～5.2222(m, 2H), 5.8968～5.9396(m, 1H), 7.4949～7.5299(m, 2H), 7.6112(m, 1H), 7.9706～8.0056(m, 2H), 8.2648～8.2844(d, 1H), 8.5801～8.5920(d, 1H) 8.8295～8.8421(d, 1H), 9.4460～9.4754(m, 1H), 13.5766(s, 1H).HLPC-MS?m/z：346.2[M+1]
+。
Embodiment 4:N-ethyl-2-bis-(pyridine-2 base) methene amido-selenourea
Method is with embodiment 1, intermediate 4-ethyl-3-selenosemicarbazide
1h-NMR(400MHz, DMSO) δ ppm:1.1452～1.0810(t, 3H), 3.4398～3.4727(m, 2H), 4.4353(m, 2H) and, 7.8185(m, 1H), 8.5474(m, 1H).Yellow solid N-ethyl-2-bis-(pyridine-2 base) methene amido-selenourea
1h-NMR(400MHz, DMSO) δ ppm:1.172～1.207(t, 3H) 3.692～3.726(m, 2H) 7.491～7.517(m, 2H), 7.595～7.614(m, 1H), 7.971～8.002(m, 2H), 8.235～8.255(d, 1H), 8.578～8.590(d, 1H), 8.823～8.835(d, 1H), 9.286～9.314(t, 1H), 13.473(s, 1H).HLPC-MS?m/z：334.3[M+1]
+。
Embodiment 5:N-phenyl-2-bis-(pyridine-2 base) methene amido-selenourea
Method is with embodiment 1, yellow solid N-phenyl-2-bis-(pyridine-2 base) methene amido-selenourea
1h-NMR(400MHz, DMSO) δ ppm:7.228～7.314(t, 1H), 7.397～7.435(t, 2H), 7.488～7.580(m, 5H), 7.630～7.635(m, 1H), 7.943～7.963(m, 1H), 8.011～8.035(m, 1H), 8.415～8.431(m.1H) and, 8.592～8.602(d, 1H), 8.853(m, 1H), 10.856(s, 1H), 13.841(s, 1H), HLPC-MS m/z:382.1[M+1]
+.
Embodiment 6:N-cyclopropyl-2-bis-(pyridine-2 base) methene amido-selenourea
Method is with embodiment 1, yellow solid N-cyclopropyl-2-bis-(pyridine-2 base) methene amido-selenourea
1h-NMR(400MHz, DMSO) δ ppm:0.800～0.811(t, 4H), 3.212～3.223(m, 1H), 7.470～7.491(m, 1H), 7.472～7.493(m, 1H), 7.957～8.015(m, 2H), 8.223～8.245(m, 1H), 8.567～8.579(m, 1H), 8.823～8.835(m, 1H), 9.084～9.095(d, 1H), 13.619(s, 1H).HLPC-MSm/z：346.0[M+1]
+。
Embodiment 7:N-cyclohexyl-2-bis-(pyridine-2 base) methene amido-selenourea
Method is with embodiment 1, intermediate 4-ethyl-3-selenosemicarbazide
1h-NMR(400MHz, DMSO) δ ppm:1.111～1.162(m, 2H), 1.212～1.338(m, 3H), 1.547～1.578(m, 1H), 1.653～1.682(m, 2H), 1.820～1.840(m, 2H), 1.01(m, 1H) 4.490(s, 2H), 7.769～7.790(d, 1H), 9.013(s, 1H).Yellow solid N-ring ethyl-2-bis-(pyridine-2 base) methene amido-selenourea
1h-NMR(400MHz, DMSO) δ ppm:1.109～1.175(m, 1H), 1.232～1.328(m, 2H), 1.466～1.565(m, 2H), 1.606～1.636(d, 1H), 1.730～1.763(d, 2H), 1.896～1.921(d, 2H), 4.269～4.290(m, 1H), 7.467～7.485(m, 1H), 7.488～7.500(m, 1H), 7.603～7.619(m, 1H), 7.892～8.004(m, 2H), 8.220～8.242(d, 1H), 8.580～8.594(m, 1H), 8.821～8.834(m, 2H), 13.509(s, 1H).HLPC-MS?m/z：388.3[M+1]
+。
Embodiment 8:N, N-dimethyl-2-bis-(pyridine-2 base) methene amido-selenourea
Step 1. two (2-pyridine) ketone contracting 4,4-dimethyl-3-thiosemicarbazide
Take 0.552g (3mmol) two (2-pyridine) ketone and 0.476g(4mmol) 4,4-dimethyl-3-thiosemicarbazide, join in 50ml single port bottle, add ethanol 10ml, glacial acetic acid 1ml, stirring heating back flow reaction 2～3h, obtains two (2-pyridine) ketone contracting 4,4-dimethyl-3-thiosemicarbazide (0.6g, 70%).
Step 2. two (2-pyridine) ketone contracting S-methyl sulfo-4,4-methyl-3-thiosemicarbazide
Take 0.86g(3mmol) two (2-pyridine) ketone contracting 4,4-dimethyl-3-thiosemicarbazide is in 50ml single port bottle, add ethanol 5ml, add again 0.57g (4mmol) CH3I. heating reflux reaction 2h. and obtain two (2-pyridine) ketone contracting S-methyl sulfo-4,4-methyl-3-thiosemicarbazide (0.72g, 80%).
1H-NMR（400MHz，DMSO）δppm：2.581（s，3H），3.048～3.078（s，6H），7.530～7.549（m，1H），7.908～7.941（t，1H），8.022～8.088（m，2H），8.176～8.196（d，1H），8.450～8.490（t，1H），8.535～8.547（d，1H），8.944～8.958（d，1H）。HLPC-MS?m/z：300.3[M+1]
+。
Step 3:N, N-dimethyl-2-bis-(pyridine-2 base) methene amido-selenourea
Take 0.9g (3mmol) two (2-pyridine) ketone contracting S-methyl sulfo-4; 4-methyl-3-thiosemicarbazide, joins in NaHSe (reacting generation by the Se of 4mmol and the NaBH4 of 5mmol under the nitrogen protection) solution of just having made.Room temperature reaction 20h, obtains N, N-dimethyl-2-bis-(pyridine-2 base) methene amido-selenourea (0.68g, 68%).
1H-NMR（400MHz，DMSO）δppm：3.471～3.537（s，6H），7.306～7.334（m，1H），7.380～7.388（m，1H），7.728～7.748（d，1H），7.816～7.840（m，2H），8.153～8.173（d，1H），8.569～8.579（d，1H），8.693～8.705（d，1H），15.317（s，1H）。HLPC-MS?m/z：334.3[M+1]
+。
Embodiment 9:N-(pyridine-2 base)-2-bis-(pyridine-2 base) methene amido-selenourea
Step 1. is prepared the amino first thioester of intermediate 2-pyridine and add 2.82g(30ml in 100ml single port bottle) diamino-pyridine and 30mlDMSO, separately take 1.98g(30mol) KOH, with the dissolving of 2ml distilled water, adding people in single port bottle, finally add 2.75g (36mmol) CS
2, after room temperature reaction 6h, add methyl iodide 4.26g(30mmol), continue room temperature reaction 7h.Aftertreatment: add 30ml distilled water, by ethyl acetate 40mlx3 extraction, organic layer anhydrous Na
2sO
4dried overnight, finally uses silica gel mixed sample, crosses silicagel column, eluent CH
2cl
2: MeOH=50:1, finally obtains yellow solid product 2.26g, productive rate 40.9%.
1H-NMR（400MHz，CDCL
3）δppm：2.687（s，3H），7.133-7.264（t，1H），7.761-7.766（t，1H），8.420-8.432（d，1H），8.435-8.4350（m，1H），10.291（s，1H）。HLPC-MS?m/z：185.0[M+1]
+。
Step 2. is prepared 4-(2-pyridyl)-3-thiosemicarbazide
In 50ml single port bottle, add the amino first thioester of 0.92g (5mmol) 2-pyridine and 10ml ethanol, adding 0.30g (5mmol, 85%) hydrazine hydrate, 85 DEG C of back flow reaction 1h, have a large amount of white solids to generate, and filter to obtain product 0.79g.
1H-NMR（400MHz，DMSO）δppm：2.234（d，2H），7.023（t，1H，7.130-7.152（d，1H），7.762-7.765（t，1H），8.218-8.234（d，1H），10.568（d，1H），12.588（d，1H）。
Step 3. is prepared two intermediates two (2-pyridine) ketone contracting 4-(2-pyridine)-3-thiosemicarbazide
In 50ml eggplant-shape bottle, add 0.09g (0.5mmol) two (2-pyridine) ketone and 0.08g (0.5mmol) 4-(2-pyridine)-3-thiosemicarbazide, add again 10ml ethanol, 10d glacial acetic acid, 85 DEG C of back flow reaction 4h. solution first become yellow from light orange, finally there is yellow solid to separate out, filtration drying obtains solid 0.14g, productive rate 83.8%.
1H-NMR（400MHz，DMSO）δppm：7.006（t，1H），7.177～7.197（d，1H），7.450～7.464（t，1H），7.534～7.553（d，1H），7.617～7.634（t，1H），7.464～7.679（m，1H），7.752～7.786（t，1H），7.785～8.026（t，1H），8.042～8.060（t，1H），8.247～8.267（d，1H），8.512（m，1H），8.893～8.904（d，1H），11.108（s，1H），15.021（s，1H）.
Step 4. is prepared intermediate two (2-pyridine) ketone contracting S-methyl sulfo-4-(2-pyridyl)-3-thiosemicarbazide
In 100ml eggplant-shape bottle, add two (2-pyridine) ketone contracting 4-(2-pyridine)-3-thiosemicarbazide 1.64g(5mmol), use 20mlCH
2cl
2it is dissolved, then add 0.78g (5.5mmol) methyl iodide, back flow reaction 3h, reaction is finished, and crosses silicagel column, and eluent ethyl acetate: sherwood oil=1:1, obtains product 0.92g, productive rate 52.6%.
1H-NMR（400MHz，DMSO）δppm：2.501～2.510（s，3H），7.049～7.047（t，1H），7.116-7.136（d，1H），7.383-7.390（m，1H），7.460-7.479（t，1H），7.549-7.568（d，1H），7.605-7.622（t，1H），7.740-7.764（t，1H），7.989-8.009（m，1H），8.057-8.076（d，1H），8.193-8.205（d，1H），8.548-8.559（d，1H），8.955-8.966（d，1H）。15.095（s，1H）。
Step 5. is prepared target compound N-(pyridine-2 base)-2-bis-(pyridine-2 base) methene amido-selenourea
In 50ml single port bottle, prepare fresh NaHSe (0.4g, 5mmol Se+0.23g6mmol NaBH
4) solution, add Na
2cO
30.53g (5mmol), separately takes 0.92g (2.6mmol) two (2-pyridine) ketone contracting S-methyl sulfo-4-(2-pyridyl)-3-thiosemicarbazide, uses 10mlCH
2cl
2after dissolving, join in there-necked flask, nitrogen protection, room temperature reaction spends the night, and reaction is finished; add 2ml glacial acetic acid, 5% NaOH solution 200ml absorbs tail gas, reacts half an hour, finally separates with silicagel column; eluent ethyl acetate: sherwood oil=1:2, obtains product 0.12g, productive rate 12.1%.
1H-NMR（400MHz，DMSO）δppm：7.06～7.09（t，1H），7.27～7.29（d，1H），7.46～7.48（t，1H），7.55～7.57（d，1H），7.63～7.66（t，1H），7.72～7.73（d，1H），7.79～7.82（t，1H），8.00～8.03（t，1H），8.05-8.07（d，1H），8.31-8.33（d，1H），8.51-8.53（d，1H），8.91-8.92（d，1H），11.53（s，1H），15.40（s，1H）。HLPC-MS?m/z：381.1[M+1]
+。
Embodiment 10:N-cyclopentyl-2-bis-(pyridine-2 base) methene amido-selenourea
Synthetic method is with embodiment 1, productive rate 37.5%,
1h-NMR(400MHz, DMSO) δ ppm:0.86～0.91(m, 1H), 1.17～1.19(m, 1H), 1.51～1.62(m, 2H), 1.64～1.75(m, 4H), 1.99～2.00(m, 2H), 4.71～4.73(m, 1H), 7.41～7.49(m, 2H), 7.63～7.69(m ,/1H), 7.98～8.00(m, 2H), 8.20～8.28(d, 1H), 8.58～8.61(d, 1H), 8.83～8.86(d, 1H), 8.89～9.01(d, 1H), 13.55(s, 1H).HLPC-MS?m/z：374.2[M+1]
+。
Embodiment 11:N-sec.-propyl-2-bis-(pyridine-2 base) methene amido-selenourea
Synthetic method is with embodiment 1, productive rate 53.8%.
1H-NMR（400MHz，DMSO）δppm：1.24-1.28（s，6H），4.61-4.63（m，1H），7.46-7.48（m，2H），7.52-7.54（m，1H），7.99-8.01（m，3H），8.21-8.23（d，1H），8.58-8.60（d，1H），8.8208.84（m，2H），13.50（s，1H）。HLPC-MS?m/z：348.3[M+1]
+。
Embodiment 12:N-butyl-2-bis-(pyridine-2 base) methene amido-selenourea
Synthetic method example 1,
1h-NMR(400MHz, DMSO) δ ppm:0.92～0.94(m, 3H), 1.32～1.34(m, 2H), 1.60～1.62(m, 2H), 3.67～3.69(m, 2H), 7.50～7.52(m, 2H), 7.60～7.64(m, 1H), 7.98～8.00(m, 2H), 8.24～8.26(d, 1H), 8.84～8.86(d, 1H), 9.30～9.32(t, 1H), 13.48(s, 1H).HLPC-MS?m/z：362.3[M+1]
+。
Embodiment 13:N-propyl group-2-bis-(pyridine-2 base) methene amido-selenourea
Synthetic method example 1, productive rate 98.5%.Productive rate 98.5%.
1H-NMR（400MHz，DMSO）δppm：0.88～0，91（m，3H），1.63～1.66（m，2H），3.62～3.66（m，2H），7.50～7.52（m，2H），7.62～7.68（m，1H），7.98-8.00（m，2H），8.25～8.27（d，1H），8.58～8.59（d，1H），8.83～8.84（d，1H），9.30～9.33（t，1H），13.49（s，1H）。HLPC-MS?m/z：348.2[M+1]
+。
Embodiment 14:N-cyclopropyl-2-(phenyl (pyridine-2-yl)) methene amido-selenourea
Synthetic method is with embodiment 1,0,36g(2mmol) phenyl-2-pyridinyl methanone and 0.43g (2.4mmol) 4-cyclopropyl-3-selenosemicarbazide react to obtain product 0.34g, productive rate 49.4%.
11H-NMR（400MHz，DMSO）δppm：0.78～0.80（m，4H），3.21～3.24（m，1H），7.30～7.36（m，1H），7.44～7.48（m，2H），7.60～7.65（m，3H），8.01～8.10（m，1H），8.53～8.55（d，1H），8.85～8.88（d，1H），9.91～9.95（m，1H），13.23（s，1H）。HLPC-MS?m/z：345.1[M+1]
+。
Embodiment 15:N-methyl-2-(phenyl (pyridine-2-yl)) methene amido-selenourea
Synthetic method is with embodiment 1,
1h-NMR(400MHz, DMSO) δ ppm:3.12～3.14(s, 3H), 7.31～7.40(m, 1H), 7.43～7.52(m, 2H), 7.64～7.68(m, 3H), 8.01～8.03(m, 1H), 8.55～8.57(d, 1H), 8.87-8.90(d, 1H), 9.11～9.13(d, 1H), 13.18(s.1H).HLPC-MS?m/z：319.2[M+1]
+。
Embodiment 16:N-allyl group-2-(phenyl (pyridine-2-yl)) methene amido-selenourea
Synthetic method is with embodiment 1,0,36g(2mmol) phenyl-2-pyridinyl methanone and 0.43g (2.4mmol) 4-cyclopropyl-3-selenosemicarbazide react to obtain product 0.34g, productive rate 49.4%.
1H-NMR（400MHz，DMSO）δppm：4.31～4.34（m，2H），5.14～5.21（m，2H），5.90～5.93（m，1H），7.37～7.39（m，1H），7.47～7.49（m，2H），7.66～7.68（m，3H），8.01～8.10（m，1H），8.87～8.89（d，1H），9.31～9.34（d，1H），13.19（s，1H）。HLPC-MS?m/z：345.1[M+1]
+。
Embodiment 17:N-sec.-propyl-2-(phenyl (pyridine-2-yl)) methene amido-selenourea
Synthetic method is with embodiment 1, and 0.36g (2mmol) phenyl-2-pyridinyl methanone reacts to obtain product 0.30g, productive rate 57.8% with 0.29g (1.5mmol) 4-sec.-propyl-3-selenosemicarbazide.
1H-NMR（400MHz，DMSO）δppm：1.25～1.28（s，6H），4.58～4.62（m，1H），7.34～7.36（m，1H），7.48～7.50（m，2H），7.63～7.65（m，3H），8.03～8.07（m，1H），8.48～8.50（m，1H），8.70～8.72（d，2H），8.87-8.89（d，1H），13.13（s，1H）。HLPC-MS?m/z：347.3[M+1]
+。
Embodiment 18:N-cyclohexyl-2-(phenyl (pyridine-2-yl)) methene amido-selenourea
Synthetic method example 1,0.92g (5mmol) phenyl-2-pyridinyl methanone reacts to obtain product 1.40g, productive rate 72.5% with 1.10g (5mmol) 4-cyclohexyl-3-selenosemicarbazide.
1H-NMR（400MHz，DMSO）δppm：1.10-1.13（m，1H），1.26～1.29（m，2H），1.49～1.55（m，3H），1.71～1.75（m，2H），1.89～1.91（m，2H），4.26～4.28（m，1H），7.31～7.35（m，1H），7.49～7.53（m，2H），7.63～7.66（m，3H），8.03～8.10（m，1H），8.50～8.54（d，1H），8.64～8.67（d，1H），8.86～8.88（d，1H），13.13（s，1H）。HLPC-MS：m/z：387.5[M+1]
+。
Embodiment 19:N-ethyl-2-(phenyl (pyridine-2-yl)) methene amido-selenourea
Synthetic method is with embodiment 1, productive rate 78.3%.0.92g (5mmol) phenyl-2-pyridinyl methanone reacts to obtain product 1.30g, productive rate 78.3% with 0.90g (5mmol) 4-ethyl-3-selenosemicarbazide.
1H-NMR（400MHz，DMSO）δppm：1.16～1.19（m，3H），3.69～3.71（m，2H），7.35～7.38（m，1H），7.47～7.49（m，3H），7.65～7.67（m，3H），8.02～8.07（m，1H），8.86～8.89（d，1H），9.18～9.20（d，1H），13.11（s，1H）。HLPC-MS?m/z：333.3[M+1]
+。
Embodiment 20:N-propyl group-2-(phenyl (pyridine-2-yl)) methene amido-selenourea
Synthetic method is with embodiment 1, productive rate 58.1%.0.92g (5mmol) phenyl-2-pyridinyl methanone reacts to obtain product 1.0g, productive rate 58.1% with 0.95g (5mmol) 4-propyl group-3-selenosemicarbazide.
1H-NMR（400MHz，DMSO）δppm：0.86～0.90（m，3H），1.63～1.66（m，2H），3.60～3.64（m，2H），7.32～7.35（m，1H），7.47～7.49（m，3H），7.65～7.67（m，3H），8.03～8.05（m，1H），8.87～8.89（d，1H），9.17～9.18（t，1H），13.11（s，1H）。HLPC-MS?m/z：347.2[M+1]
+。
Embodiment 21:N-cyclopentyl-2-(phenyl (pyridine-2-yl)) methene amido-selenourea
Synthetic method is with embodiment 1, and 0.9g (4.9mmol) phenyl-2-pyridinyl methanone reacts to obtain product 1.10g, productive rate 60.4% with 1.0g (5mmol) 4-cyclopentyl-3-selenosemicarbazide.
1H-NMR（400MHz，DMSO）δppm：1.52～1.80（m，6H），2.18～2.21（m，2H），7.21～7.26（m，2H），7.47～7.53（m，5H），7.75～7.78（m，1H），7.91～7.99（d，1H），8.84～8.85（d，1H），13.99（s，1H）。HLPC-MS：m/z：373.1[M+1]
+。
Embodiment 22:N-cyclopentyl-2-(phenyl (pyrimidine-2-base)) methene amido-selenourea
Synthetic method is with embodiment 1, and 0.27g0 (1.5mmol) phenyl-2-pyrimidine ketone reacts to obtain product 0.36g, productive rate 64.4% with 0.41g (2mmol) 4-cyclopentyl-3 selenosemicarbazide.
1H-NMR（400MHz，DMSO）δppm：1.51～1.54（m，2H），1.67～1.72（m，4H），1.98～12.02（m，2H），4.72～4.74（m，1H），7.42～7.43（m，3H），7.64～7.68（m，3H），8.85～8.86（d，2H），9.07～9.08（d，2H），12.91（s，1H）。HLPC-MS?m/z：395.6[M+Na]
+。
Embodiment 23:N-propyl group-2-(phenyl (pyrimidine-2-base)) methylamino-selenourea
Synthetic method is with embodiment 1, and 0.92g (5mmol) phenyl-2-pyrimidine ketone reacts to obtain product 0.80g, productive rate 46.2% with 0.91g (5mmol) 4-propyl group-3-selenosemicarbazide.
1H-NMR（400MHz，DMSO）δppm：0.99-1.03（m，3H），1.74～1.78（m，2H），3.78～3.80（m，2H），7.39～7.45（m，4H），7.58～7.62（m，2H），8.15～8.20（m，1H），8.96～8.98（d，2H），13.80（s，1H）。HLPC-MSm/z：348.1[M+1]
+。
Embodiment 24:N-ethyl-2-(phenyl (pyrimidine-2-base)) methene amido-selenourea
Synthetic method is with embodiment 1, and 0.92g (5mmol) phenyl-2-pyrimidine ketone reacts to obtain product 1.50g, productive rate 90.0% with 0.84g (5mmol) 4-ethyl-3-selenosemicarbazide.
1H-NMR（400MHz，DMSO）δppm：1.16～1.20（m，3H），3.70～3.74（m，2H），7.40～7.42（m，3H），7.67～7.68（m，3H），9.07～9.09（m，2H），9.27～9.28（m，1H），12.87（s，1H）。HLPC-MS?m/z：334.1[M+1]
+。
Embodiment 25:N-cyclohexyl-2-(phenyl (pyrimidine-2-base)) methene amido-selenourea
Synthetic method is with embodiment 1, and 0.92g (5mmol) phenyl-2-pyrimidine ketone reacts to obtain product 1.50g, productive rate 77.4% with 0.11g (5mmol) 4-cyclohexyl-3-selenosemicarbazide.
1H-NMR（400MHz，DMSO）δppm：1.12～1.18（m，1H），1.27～1.30（m，2H），1.51～1.54（m，2H），1.60～1.64（m，1H），1.75，1.79（m，2H），1.90～1.94（m，2H），4.28～4.30（m，1H），7.42～7.44（m，3H），7.64～7.68（m，3H），8.74～8.76（d，1H），9.07～9.08（d，2H），12.89（s，1H）。HLPC-MS?m/z：388.2[M+1]
+。
Embodiment 26:N-allyl group-2-(phenyl (pyrimidine-2-base)) methylene amino-selenourea
Synthetic method is with embodiment 1, and 0.55g (3mmol) phenyl-2-pyrimidine ketone and 0.53g (3mmol) 4-allyl group-3-selenosemicarbazide obtain product 0.7g, productive rate 67.3%.
1H-NMR（400MHz，DMSO）δppm：4.33～4.36（m，2H），5.12～5.15（m，2H），5.90～5.94（m，1H），7.40～7.42（m，3H），7.67～7.69（m，3H），9.08～9.09（d，2H），9.40～9.41（m，1H），12.94（s，1H.)。HLPC-MSm/z：346.1[M+1]
+。
Embodiment 27:N-sec.-propyl-2-(phenyl (pyrimidine-2-base)) methene amido-selenourea
Synthetic method is with embodiment 1,0.92g (5mmol) phenyl-2-pyrimidine ketone and 0.97g(5mmol) 4-sec.-propyl-3-selenosemicarbazide reacts to obtain product 1.46g, productive rate 83.9%.
1H-NMR（400MHz，DMSO）δppm：1.34～1.38（m，6H），4.74～4.76（m，1H），7.40～7.46（m，3H），7.58～7.60（m，3H），7.91～7.95（d，1H），8.96～8.98（m，2H），13.75（s，1H）。HLPC-MS?m/z：348.1[M+1]
+。
Embodiment 28:N-methyl-2-(phenyl (pyrimidine-2-base)) methene amido-selenourea
Synthetic method is with embodiment 1, and 0.92g (5mmol) phenyl-2-pyrimidine ketone and 0.76g (5mmol) 4-methyl-3-selenosemicarbazide obtain product 1.30g, productive rate 81.3%.
1H-NMR（400MHz，DMSO）δppm：3.13～3.14（m，3H），7.40～7.42（m，3H），9.07～9.09（m，2H），9.21～9.23（m，1H），12.93（s，1H）。HLPC-MS?m/z：320.1[M+1]
+。
Embodiment 29:N-cyclopropyl-2-(phenyl (pyrimidine-2-base)) methene amido-selenourea
Synthetic method is with embodiment 1, and 0.92g (5mmol) phenyl-2-pyrimidine ketone produces and reacts to obtain product 1.36g, productive rate 78.6% with 0.89g (5mmol) 4-cyclopropyl-3-selenosemicarbazide.
1H-NMR（400MHz，DMSO）δppm：0.78～0.8（m，4H），3.23～3.24（m，1H），7.39～7.41（m，3H），7.64～7.68（m，3H），9.05～9.08（m，3H），12.97（s，1H），HLPC-MS?m/z：346.1[M+1]
+。
Embodiment 30:N-butyl-2-(phenyl (pyrimidine-2-base)) methene amido-selenourea
Synthetic method example 1, productive rate 83.3%.0.92g (5mmol) phenyl-2-pyrimidine ketone reacts to obtain product 1.5g, productive rate 83.3% with 0.98g (5mmol) 4-butyl-3-selenosemicarbazide.
1H-NMR（400MHz，DMSO）δppm：0.97～0.99（m，3H），1.44～1.50（m，2H），1.71～1.75（m，2H），3.81～3.83（m，2H），7.39～7.45（m，4H），7.51～7.56（d，1H），8.96～8.97（d，2H），13.79（s，1H）。HLPC-MSm/z：361.08[M+1]
+。
Embodiment 31: the impact of embodiment compound on tumour cell survival
The selection of cell for experiment
Every kind of compound is selected the responsive control cells BT474 of lapatinibditosylate and SK-BR3, lapatinibditosylate secondary persister BT/Lap
r1.0 and SK/Lap
r1.0, to lapatinibditosylate natural drug resistance strain MDA-MB-361, MDA-MB-453 totally 6 strain cells as screening experiment cell.
Cell cultures
Tumour cell recovers growth slowly from the state of cryopreservation, probably needs cover with the 100mm culture dish of 70-80% 1-2 time in week.
To cover with the 100mm culture dish of tumour cell, with 37 DEG C of digestion 1min of 1ml0.25% pancreatin (GIBCO), 2ml RPMI-1640 or DMEM(are containing 10%FBS, GIBCO) termination reaction, dispel collecting cell 1:3 or 1:4 and go down to posterity, add fresh culture, approximately go down to posterity 1-2 time weekly.
Determining of screening compound concentration
Each compound to be checked selects concentration 5 μ M to be used for testing detection; The mensuration of IC50 value: testing sample is diluted to final concentration is 50,25,12.5,6.25,3.125,1.56,0.78,0.39,0nM, control wells is for adding substratum, and each concentration is established 3 parallel holes, and every hole 50uL is hatched 72h for 37 DEG C.
Cell bed board
To cover with the 100mm culture dish of attached cell, with 37 DEG C of digestion 5min of 1ml0.25% pancreatin (GIBCO), 2ml substratum (containing 10%FBS, GIBCO) termination reaction, dispels collecting cell, is diluted to 1 × 10 after counting
5cells/ml, 50 μ l/ holes, 5000cells/well, is inoculated in 96 orifice plates, make a circle outward remove do not add cell, add PBS, 60 holes altogether, 37 DEG C, hatch 24 hours adherent.
Add compound
Testing sample is diluted to final concentration, and control wells is the substratum that adds respective compound solvent strength, and every hole compound solvent strength is consistent, and each concentration is established 5 parallel holes, and every hole 25uL, fills 25uL substratum, hatches 72h for 37 DEG C.
After hatching 72h, detect
Every hole adds the ATPlite test kit substrate solution of 50 μ l, concussion 3min, and lucifuge leaves standstill 10min; Draw cracking supernatant 100 μ l/ holes, in luminescent screen; The luminescent screen of hatching is put into light-emitting appearance, read luminous value.
Data processing
Cell survival rate (%)=experimental group RLU/ blank group RLU × 100%
Utilize GraphPad software to carry out data analysis and processing to experimental data.
Distribute taking compound concentration as X-coordinate and with logarithmic form, inhibiting rate is coordinate mapping, and with the matched curve of Logistic4 parametric equation, the compound concentration that on curve, 50% inhibiting rate is corresponding is IC50 value.
Embodiment compound is as follows to activity of tumor cells result:
The effect of the routine compound of table 1. to 6 kinds of different tumour cell survivals
The IC of table 2. compound
50value
Embodiment 32: the synergism of embodiment compound to lapatinibditosylate
The selection of cell for experiment
Every kind of compound is selected lapatinibditosylate secondary persister BT/Lap
r1.0 and SK/Lap
r1.0, to lapatinibditosylate natural drug resistance strain MDA-MB-361, MDA-MB-453 totally 4 strain cells as screening experiment cell.
Cell cultures
Tumour cell recovers growth slowly from the state of cryopreservation, probably needs cover with the 100mm culture dish of 70-80% 1-2 time in week.
To cover with the 100mm culture dish of tumour cell, with 37 DEG C of digestion 1min of 1ml0.25% pancreatin (GIBCO), 2ml RPMI-1640 or DMEM(are containing 10%FBS, GIBCO) termination reaction, dispel collecting cell 1:3 or 1:4 and go down to posterity, add fresh culture, approximately go down to posterity 1-2 time weekly.
Determining of screening compound concentration
Each embodiment compound selects concentration 5 μ M to be used for testing detection, and lapatinibditosylate concentration is that 1 μ M is for testing detection; After each embodiment compound and lapatinibditosylate mix, embodiment compound final concentration is that 5 μ M, lapatinibditosylate final concentration are that 1 μ M is for testing detection.
Cell bed board
To cover with the 100mm culture dish of attached cell, with 37 DEG C of digestion 5min of 1ml0.25% pancreatin (GIBCO), 2ml substratum (containing 10%FBS, GIBCO) termination reaction, dispels collecting cell, is diluted to 1 × 10 after counting
5cells/ml, 50 μ l/ holes, 5000cells/well, is inoculated in 96 orifice plates, make a circle outward remove do not add cell, add PBS, 60 holes altogether, 37 DEG C, hatch 24 hours adherent.
Add compound and lapatinibditosylate
Testing sample is diluted to final concentration, control wells is the substratum that adds respective compound solvent strength, every hole compound solvent strength is consistent, each concentration is established 5 parallel holes, every hole 25uL, add that 25uL lapatinibditosylate to lapatinibditosylate final concentration is 1 μ M, the total concn of embodiment compound is 5 μ M, hatches 72h for 37 DEG C simultaneously.
After hatching 72h, detect
Every hole adds the ATPlite test kit substrate solution of 50 μ l, concussion 3min, and lucifuge leaves standstill 10min; Draw cracking supernatant 100 μ l/ holes, in luminescent screen; The luminescent screen of hatching is put into light-emitting appearance, read luminous value.
Data processing
Cell survival rate (%)=experimental group RLU/ blank group RLU × 100%
Utilize GraphPad software to carry out data analysis and processing to experimental data.
Distribute taking compound concentration as X-coordinate and with logarithmic form, inhibiting rate is coordinate mapping.
Result is judged:
Adopt two medicine interaction indexes (coefficient of drug interaction, CDI) to evaluate two medicine interactive properties, CDI calculates by following formula: CDI=AB/(A × B) × 100.Calculate according to viable count (luminous value), in the time of CDI<1, two medicine interaction properties are for collaborative; In the time of CDI<0.7, synergy highly significant.
Table 3. embodiment compound and the effect of lapatinibditosylate coupling to drug-resistant tumor cell survival
Conclusion:
Embodiment compound all has restraining effect very significantly to the survival rate of 6 kinds of different tumour cells, particularly the effect of the tumour cell to resistance is obviously better than existing clinical treatment medicine lapatinibditosylate, and effect have greatly improved, embodiment compound 8 and 15 and lapatinibditosylate combined utilization after there is synergism significantly.
Claims (13)
1. the compound shown in formula II,
Or its isomer, pharmacy acceptable salt, wherein
X
1, X
2, X
3and X
4independently selected from C or N;
R
3and R
4independently selected from hydrogen, hydroxyl, halogen, amino, nitro, trifluoromethyl, C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl, C
6-C
10aryl or there is the heteroaryl of 5～10 atoms, this heteroaryl has at least one heteroatoms independently selected from N, O or S, wherein said alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl or heteroaryl are optionally replaced by one or more substituting groups, and this substituting group is independently selected from hydroxyl, halogen, amino, nitro, trifluoromethyl, C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl or C
3-C
10cycloalkyl; And
R
8and R
9independently selected from hydrogen, hydroxyl, halogen, amino, nitro, trifluoromethyl, C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl or C
3-C
10cycloalkyl.
2. compound claimed in claim 1, wherein
X
1, X
2, X
3and X
4independently selected from C or N;
R
3and R
4independently selected from hydrogen, hydroxyl, halogen, amino, nitro, trifluoromethyl, C
1-C
6alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
3-C
8cycloalkyl, phenyl or there is the heteroaryl of 5～7 atoms, this heteroaryl has at least one heteroatoms independently selected from N, O or S; And
R
8and R
9be hydrogen independently.
3. the compound shown in formula III,
Or its isomer, pharmacy acceptable salt, wherein
X
1, X
2, X
3and X
4independently selected from C or N;
R
3and R
4independently selected from hydrogen, hydroxyl, halogen, amino, nitro, trifluoromethyl, C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl, C
6-C
10aryl or there is the heteroaryl of 5～10 atoms, this heteroaryl has at least one heteroatoms independently selected from N, O or S, wherein said alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl or heteroaryl are optionally replaced by one or more substituting groups, and this substituting group is independently selected from hydroxyl, halogen, amino, nitro, trifluoromethyl, C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl or C
3-C
10cycloalkyl; And
R
8and R
9independently selected from hydrogen, hydroxyl, halogen, amino, nitro, trifluoromethyl, C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl or C
3-C
10cycloalkyl.
4. compound claimed in claim 3, it is the compound shown in formula IV,
Or its isomer, pharmacy acceptable salt, wherein
X
1, X
2, X
3and X
4independently selected from C or N;
R
3and R
4independently selected from hydrogen, hydroxyl, halogen, amino, nitro, trifluoromethyl, C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl, C
6-C
10aryl or there is the heteroaryl of 5～10 atoms, this heteroaryl has at least one heteroatoms independently selected from N, O or S, wherein said alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl or heteroaryl are optionally replaced by one or more substituting groups, and this substituting group is independently selected from hydroxyl, halogen, amino, nitro, trifluoromethyl, C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl or C
3-C
10cycloalkyl; And
R
8and R
9independently selected from hydrogen, hydroxyl, halogen, amino, nitro, trifluoromethyl, C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl or C
3-C
10cycloalkyl.
5. compound claimed in claim 3, it is the compound shown in formula V,
Or its isomer, pharmacy acceptable salt, wherein
X
1, X
2, X
3and X
4independently selected from C or N; And
R
3and R
4independently selected from hydrogen, hydroxyl, halogen, amino, nitro, trifluoromethyl, C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl, C
6-C
10aryl or there is the heteroaryl of 5～10 atoms, this heteroaryl has at least one heteroatoms independently selected from N, O or S, wherein said alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl or heteroaryl are optionally replaced by one or more substituting groups, and this substituting group is independently selected from hydroxyl, halogen, amino, nitro, trifluoromethyl, C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl or C
3-C
10cycloalkyl.
6. the compound of claim 3, it is the compound shown in formula V,
Or its isomer, pharmacy acceptable salt, wherein
X
1, X
2, X
3and X
4independently selected from C or N; And
R
3and R
4independently selected from hydrogen, hydroxyl, halogen, amino, nitro, trifluoromethyl, C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl, phenyl or have the heteroaryl of 5～7 atoms, this heteroaryl has at least one heteroatoms independently selected from N, O or S.
7. the compound of claim 3, it is the compound shown in formula V,
Or its isomer, pharmacy acceptable salt, wherein
X
1, X
2, X
3and X
4independently selected from C or N; And
R
3and R
4independently selected from hydrogen, hydroxyl, halogen, amino, nitro, trifluoromethyl, C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl, phenyl or pyridyl.
8. the compound of claim 3, it is the compound shown in formula V,
Or its isomer, pharmacy acceptable salt, wherein
X
1, X
2, X
3and X
4independently selected from C or N; And
R
3and R
4independently selected from hydrogen, hydroxyl, halogen, amino, nitro, trifluoromethyl, C
1-C
6alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
3-C
8cycloalkyl, phenyl or pyridyl.
9. the compound of claim 3, it is the compound shown in formula V,
Or its isomer, pharmacy acceptable salt, wherein
X
1, X
2, X
3and X
4independently selected from C or N; And
R
3and R
4independently selected from hydrogen, amino, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, vinyl, allyl group, propenyl, butenyl, alkene butyl, phenyl or pyridyl.
10. compound, it is selected from the compound of lower group:
2-bis-(pyridine-2 base) methene amido-selenourea
N-methyl-2-bis-(pyridine-2 base) methene amido-selenourea
N-ethyl-2-bis-(pyridine-2 base) methene amido-selenourea
N-allyl group-2-bis-(pyridine-2 base) methene amido-selenourea
N-phenyl-2-bis-(pyridine-2 base) methene amido-selenourea
N-cyclopropyl-2-bis-(pyridine-2 base) methene amido-selenourea
N-cyclohexyl-2-bis-(pyridine-2 base) methene amido-selenourea
N, N-dimethyl-2-bis-(pyridine-2 base) methene amido-selenourea
N-(pyridine-2 base)-2-bis-(pyridine-2 base) methene amido-selenourea
N-cyclopentyl-2-bis-(pyridine-2 base) methene amido-selenourea
N-cyclopropyl-2-(phenyl (pyridine-2-yl)) methene amido-selenourea
N-methyl-2-(phenyl (pyridine-2-yl)) methene amido-selenourea
N-allyl group-2-(phenyl (pyridine-2-yl)) methene amido-selenourea
N-sec.-propyl-2-(phenyl (pyridine-2-yl)) methene amido-selenourea
N-sec.-propyl-2-bis-(pyridine-2 base) methene amido-selenourea
N-butyl-2-bis-(pyridine-2 base) methene amido-selenourea
N-cyclohexyl-2-(phenyl (pyridine-2-yl)) methene amido-selenourea
N-ethyl-2-(phenyl (pyridine-2-yl)) methene amido-selenourea
N-propyl group-2-bis-(pyridine-2 base) methene amido-selenourea
N-propyl group-2-(phenyl (pyridine-2-yl)) methene amido-selenourea
N-cyclopentyl-2-(phenyl (pyridine-2-yl)) methene amido-selenourea
N-cyclopentyl-2-(phenyl (pyrimidine-2-base)) methene amido-selenourea
N-propyl group-2-(phenyl (pyrimidine-2-base)) methylamino-selenourea
N-ethyl-2-(phenyl (pyrimidine-2-base)) methene amido-selenourea
N-cyclohexyl-2-(phenyl (pyrimidine-2-base)) methene amido-selenourea
N-allyl group-2-(phenyl (pyrimidine-2-base)) methylene amino-selenourea
N-sec.-propyl-2-(phenyl (pyrimidine-2-base)) methene amido-selenourea
N-methyl-2-(phenyl (pyrimidine-2-base)) methene amido-selenourea
N-butyl-2-(phenyl (pyrimidine-2-base)) methene amido-selenourea
N-cyclopropyl-2-(phenyl (pyrimidine-2-base)) methene amido-selenourea,
Or their pharmacy acceptable salt.
11. 1 kinds of pharmaceutical compositions, the compound that it comprises claim 1～10 any one, and at least one pharmaceutically acceptable carrier.
12. 1 kinds of pharmaceutical compositions, its compound that comprises claim 1～10 any one, one or more are for Buddhist nun's series antineoplastic medicament and at least one pharmaceutically acceptable carrier.
The compound of 13. claim 1～10 any one is in the purposes of preparing in medicine, and wherein said medicine is used for the treatment of experimenter's tumour.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1891701A (en) * | 2005-07-07 | 2007-01-10 | 桑迪亚医药技术（上海）有限责任公司 | Heteraromatic ring thiosemicarbazone compound, and its derivatives and their use forpreparing antitumour medicine |
| CN1907970A (en) * | 2005-08-04 | 2007-02-07 | 桑迪亚医药技术（上海）有限责任公司 | Method for synthesizing heteroaryl thiosemicarbazone antineoplastic |
| CN1948304A (en) * | 2005-10-12 | 2007-04-18 | 桑迪亚医药技术（上海）有限责任公司 | Heteraryl ring thiosemicarbazone kind compound and its derivative |
| WO2012079128A1 (en) * | 2010-12-17 | 2012-06-21 | Des R Richardson | Thiosemicarbazone compounds and use in the treatment of cancer |
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2013
- 2013-05-23 CN CN201310194130.9A patent/CN104177288B/en active Active
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1891701A (en) * | 2005-07-07 | 2007-01-10 | 桑迪亚医药技术（上海）有限责任公司 | Heteraromatic ring thiosemicarbazone compound, and its derivatives and their use forpreparing antitumour medicine |
| CN1907970A (en) * | 2005-08-04 | 2007-02-07 | 桑迪亚医药技术（上海）有限责任公司 | Method for synthesizing heteroaryl thiosemicarbazone antineoplastic |
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| HULS, R等: "Selenosemicarbazide and derivatives. II. Selenosemi-carbazones and 4-phenylselenosemicarbazones， Bulletin des Societes Chimiques Belges", 《BULLETIN DES SOCIETES CHIMIQUES BELGES》 * |
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