CN103965172A - Compound and method for treating estrogen receptor-related diseases - Google Patents
Compound and method for treating estrogen receptor-related diseases Download PDFInfo
- Publication number
- CN103965172A CN103965172A CN201410189817.8A CN201410189817A CN103965172A CN 103965172 A CN103965172 A CN 103965172A CN 201410189817 A CN201410189817 A CN 201410189817A CN 103965172 A CN103965172 A CN 103965172A
- Authority
- CN
- China
- Prior art keywords
- compound
- cancer
- cell
- reaction
- benzopyran
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 0 CC(C)(*)CCc(c(*)cc(O*)c12)c1OC(c(cc1O*)ccc1O*)=C(*)C2=* Chemical compound CC(C)(*)CCc(c(*)cc(O*)c12)c1OC(c(cc1O*)ccc1O*)=C(*)C2=* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a compound and a method for treating estrogen receptor-related diseases. The present invention relates to the compound represented by the following formula (I). The compound or medicinal salt thereof is used for preventing or treating diseases involving abnormal cell proliferation related to ER-alpha in a main body.
Description
The application is the divisional application that application number is 200910180487.5, the applying date is on October 16th, 2009, denomination of invention is the Chinese invention patent application of " compounds and methods for the treatment of estrogen receptor relative disease ", original application is the Chinese invention patent application of the right of priority of September 11, application number in 2009 U.S. Provisional Application that is 12/558,392 for requiring the applying date.
Technical field
The present invention relates to prevent and/or treat compound, pharmaceutical composition and the using method thereof of the disease relevant to estrogen receptor.
Technical background
Oestrogenic hormon is one group of hormone that relates to many crucial physiological functions in human body.Estrogenic function comprise promote that female sexual organ is grown, mammary gland when conceived and uterus and puerperal breast-feeding carry out adequate preparation.Oestrogenic hormon also plays an important role maintaining aspect suitable cardiovascular function and bone density.As everyone knows, oestrogenic hormon can stimulate cellular proliferation, and may increase women thus and suffer from danger, particularly mammary cancer and the uterus carcinoma of cancer.
Oestrogenic hormon is by combining to regulate cell function with the estrogen receptor in target cell.Two kinds of estrogen receptor (hERs) in human body cell, are found, hER-α and hER-β.They have similar protein structure, and every kind all has interactional functional domain of three independences: N-terminal structural domain (A/B structural domain), middle segment DNA binding domains (C-structure territory) and C-terminal ligand binding domains (D/E/F structural domain).N-terminal structural domain has non-ligand dependent mobilizing function (AF-1), and incitant interacts together, is lacking transcriptional activation target gene in part situation.DNA binding domains has vital role aspect being combined at receptor dimerization and with specific dna sequence.C-terminal ligand binding domains can mediate ligand binding and have ligand dependent transcriptional activation function (AF-2), can in the time that part exists, transcribe by activated gene.
The hER-α of total length is that molecular weight is the albumen of 66kDa, is called as hER-α 66.HER-α 66 comprises whole three kinds of functional domains.People had found again the splicing variants of hER-α 66 afterwards, by its called after hER-α 46.The molecular weight of hER-α 46 is about 46kDa, and it lacks the N-terminal AF-1 structural domain of hER-α 66.Find again recently the varient of the hER-α of a new 36kDa, hER-α 36.N-terminal AF-1 structural domain and C that it lacks hER-α 66 hold AF-2 structural domain (referring to people such as Wang, Biochem.Biophys.Res.Commun.336,1023-1027 (2005)).
It has been generally acknowledged that hER-α 66 mediates by its target gene of transcriptional activation the cell proliferation that oestrogenic hormon stimulates.The combination of oestrogenic hormon and hER-α 66 can activate the transcriptional activation domain of hER-α 66, thereby stimulates the expression of downstream target gene, and finally causes cell proliferation.HER-α 46 is proved to be the quick NO synthetic (referring to people such as Li, Proc.Natl.Acad.Sci.USA100:4807-4812 (2003)) that can mediate by film starts and oestrogenic hormon stimulates.And the hER-α 46 that has also found disappearance AF-1 structural domain can suppress the AF-1 activity (referring to Flouriot, G., EMBO, 19,4688-4700, (2000)) of hER-α 66.Because hER-α 36 lacks AF-1 and AF-2 transcriptional activation domain, can set it as AF-1 and AF-2 function that dominant negative inhibitor suppresses hER-α and hER-β.In addition, hER-α 36 is mainly distributed on cytolemma, and mitotic division oestrogenic hormon signal that what mediation can stimulate cellular proliferation started by film (referring to people such as Wang, Biochem.Biophys.Res.Commun.336,1023-1027 (2005); The people such as Wang, Proc.Natl.Acad.Sci.U.S.A.103:9063-9068 (2006)).
Further investigation shows, oestrogenic hormon signal is that the signal transduction pathway starting by traditional nucleus transcriptional activation path and unconventional film mediates.HER-α 66 and hER-α 46 seem mainly in nucleus, to work, and hER-α 36 is mainly by working outward at nucleus.
Research shows, hER-α 36 lack original hER-α 66 with the spiral 8-12 of ligand binding domains, this has changed the specificity of hER-α 36 ligand bindings completely.Therefore, hER-α 36 can be in conjunction with the different ligands from hER-α 66 and hER-β.
Because the disease relevant to oestrogenic hormon and estrogen receptor still affects many people, current urgent need finds a kind of novel, for preventing and/or treating compound and the method for these diseases.
Invention brief introduction
In a certain embodiment, the invention provides a kind of compound and derivative thereof, pharmaceutical composition and using method, for regulating the function of novel estrogen receptor varient ER-α 36.In a certain embodiment, the invention provides a kind of compound and derivative thereof, pharmaceutical composition and using method, for preventing and/or treating the disease being mediated by ER-α 36.In a certain embodiment, the invention provides a kind of compound and derivative thereof, pharmaceutical composition and using method, for inducing cell death and/or suppress cell proliferation, and prevent and/or treat the disease of cells involved abnormality proliferation, as cancer etc.In a certain embodiment, a kind of compound and derivative thereof, pharmaceutical composition and using method are the present invention further provides, for preventing and/or treating osteoporosis, asthma and other respiratory tract disease.
In certain embodiments, the invention provides the compound for regulating ER-α 36 functions.In certain embodiments, the invention provides the method that uses the compounds of this invention to regulate ER-α 36 functions.In certain embodiments, the invention provides the method that prevents and/or treats the disease being caused by function or the dysfunction of ER-α 36.
In certain embodiments, the invention provides the compound for inducing cell death.In certain embodiments, the invention provides the method that uses compound inducing cell death of the present invention.
In certain embodiments, the invention provides the compound for suppressing cell proliferation.In certain embodiments, the invention provides the method that uses compound of the present invention to suppress cell proliferation.
In certain embodiments, the invention provides the compound for preventing and/or treating cells involved abnormal hyperplasia.In certain embodiments, the invention provides and in a main body, use compound of the present invention to prevent and/or treat the method for cells involved abnormal hyperplasia.
In certain embodiments, the invention provides the compound for preventing and/or treating asthma and other respiratory tract disease.In certain embodiments, the invention provides and in a main body, use compound of the present invention to prevent and/or treat the method for asthma and other respiratory tract disease.
In certain embodiments, the invention provides and can prevent and/or treat osteoporotic compound.In certain embodiments, the invention provides and in a main body, use compound of the present invention to prevent and/or treat the method for osteoporosis asthma.
In certain embodiments, the invention provides the pharmaceutical composition that contains compound of the present invention.
Summary of the invention
Compound and derivative thereof
By some embodiment, the application has described a compounds and derivative thereof, and pharmaceutical composition, for regulating the function of new estrogen receptor ER-α 36, prevent and/or treat the disease being mediated by ER-α 36, inducing cell death, suppress cell proliferation, prevent and/or treat the disease of cells involved abnormality proliferation, as cancer etc., and/or prevent and/or treat osteoporosis, asthma and other respiratory tract disease.
In certain embodiments, described suc as formula compound shown in (I):
And steric isomer or prodrug, or the pharmaceutically useful salt of the one of described compound, steric isomer or prodrug, wherein
X=H, OR
1or NR
2r
3; Y=NR, O; R
1, R
2, R and R
3respectively hydrogen, (C1-C6) alkyl or R
2r
3be jointly-(CH
2)
n-, n=2 to 8; Between carbon a and b or d and e, can be singly-bound or two key.R
4, R
5, R
6, R
7, R
8respectively hydrogen, halogen, hydroxyl, amino, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
1-C
6) alkoxyl group, (C
1-C
6) alkyl-(C=O)-, formyl radical, formamido-, cyano group, nitro, (C
1-C
6) carbalkoxy, aminocarboxyl, amino (C
1-C
6) alkyl, N-(C
1-C
6) alkyl amino-carbonyl, N, N-[(C
1-C
6) alkyl]
2aminocarboxyl, N-(C
6-C
10) aromatic yl aminocarbonyl, N, N-[(C
6-C
10) aryl]
2aminocarboxyl, N-(C
1-C
6) alkyl-N-(C
1-C
6) alkyl amino-carbonyl, N-(C
1-C
6) alkyl-N-(C
6-C
10) aromatic yl aminocarbonyl, aryl (comprising the aryl of replacement), (C
6-C
10) aryloxy, heteroaryl (comprising the heteroaryl of replacement), (C
5-C
9) heteroaryl oxygen base, morpholino-carbonyl, (C
1-C
6) alkoxy amino carbonyl, (C
1-C
6) alkyl-carbonylamino, (C
3-C
8) cycloalkyl, (C
3-C
8) cycloalkyl-methyl, (C
3-C
8) Heterocyclylalkyl, (C
3-C
8) Heterocyclylalkyl-methyl.R
9, R
10, R
11, R
12, and R
13respectively hydrogen, halogen, hydroxyl, (C
1-C
6) alkyl.
As R, R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, R
11, R
12, R
13for (C
1-C
6) when alkyl, (C
1-C
6) each carbon atom of alkyl can replace respectively by one to three substituting group, substituent can be selected from respectively hydroxyl, halogen, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
1-C
6) alkoxyl group, (C
1-C
6) alkyl-(C=O)-, formyl radical, formamido-, cyano group, nitro, HO-(C=O)-, (C
1-C
6) carbalkoxy, aminocarboxyl, amino (C
1-C
6) alkyl, N-(C
1-C
6) alkyl amino-carbonyl, N, N-[(C
1-C
6) alkyl]
2aminocarboxyl, N-(C
6-C
10) aromatic yl aminocarbonyl, N, N-[(C
6-C
10) aryl]
2aminocarboxyl, N-(C
1-C
6) alkyl-N-(C
1-C
6) alkyl amino-carbonyl, N-(C
1-C
6) alkyl-N-(C
6-C
10) aromatic yl aminocarbonyl, (C
6-C
10) aryl, (C
6-C
10) aryloxy, (C
5-C
9) heteroaryl, (C
5-C
9) heteroaryl oxygen base, morpholino-carbonyl, (C
1-C
6) alkoxy amino carbonyl, (C
1-C
6) alkyl-carbonylamino, (C
3-C
8) cycloalkyl, (C
3-C
8) cycloalkyl-methyl, (C
3-C
8) Heterocyclylalkyl, (C
3-C
8) Heterocyclylalkyl-methyl.
In a certain embodiment, the present invention includes the compound of one group of belt (I) structure, be called Compound I A1, the chemical formula of wherein said compound is as follows:
Wherein:
(C
6-C
10) aryl, (C
5-C
9) heteroaryl, X=H, OR
1or NR
2r
3; Y=NR, O; Wherein R, R
1, R
2and R
3respectively hydrogen, (C
1-C
6) alkyl or R
2r
3common Wei – (CH
2)
n–, n=2 to 8; Key in the middle of carbon a and b or d and e may be singly-bound or two key.R
4, R
5, R
6, R
7, R
14and R
15respectively hydrogen, halogen, hydroxyl, amino, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
1-C
6) alkoxyl group, (C
1-C
6) alkyl-(C=O)-, formyl radical, formamido-, cyano group, nitro, (C
1-C
6) carbalkoxy, aminocarboxyl, amino (C
1-C
6) alkyl, N-(C
1-C
6) alkyl amino-carbonyl, N, N-[(C
1-C
6) alkyl]
2aminocarboxyl, N-(C
6-C
10) aromatic yl aminocarbonyl, N, N-[(C
6-C
10) aryl]
2aminocarboxyl, N-(C
1-C
6) alkyl-N-(C
1-C
6) alkyl amino-carbonyl, N-(C
1-C
6) alkyl-N-(C
6-C
10) aromatic yl aminocarbonyl, (C
6-C
10) aryl (comprising the aryl of replacement), (C
6-C
10) aryloxy, (C
5-C
9) heteroaryl (comprising the heteroaryl of replacement), (C
5-C
9) heteroaryl oxygen base, morpholino-carbonyl, (C
1-C
6) alkoxy amino carbonyl, (C
1-C
6) alkyl-carbonylamino, (C
3-C
8) cycloalkyl, (C
3-C
8) cycloalkyl-methyl, (C
3-C
8) Heterocyclylalkyl, (C
3-C
8) Heterocyclylalkyl-methyl.R
9, R
10, R
11, R
12and R
13respectively hydrogen, halogen, hydroxyl, (C
1-C
6) alkyl;
As R, R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
9, R
10, R
11, R
12, R
13, R
14and R
15for (C
1-C
6) when alkyl, (C
1-C
6) each carbon atom of alkyl can replace respectively by one to three substituting group, substituting group can be selected from respectively hydroxyl, halogen, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
1-C
6) alkoxyl group, (C
1-C
6) alkyl-(C=O)-, formyl radical, formamido-, cyano group, nitro, HO-(C=O)-, (C
1-C
6) carbalkoxy, aminocarboxyl, amino (C
1-C
6) alkyl, N-(C
1-C
6) alkyl amino-carbonyl, N, N-[(C
1-C
6) alkyl]
2aminocarboxyl, N-(C
6-C
10) aromatic yl aminocarbonyl, N, N-[(C
6-C
10) aryl]
2aminocarboxyl, N-(C
1-C
6) alkyl-N-(C
1-C
6) alkyl amino-carbonyl, N-(C
1-C
6) alkyl-N-(C
6-C
10) aromatic yl aminocarbonyl, (C
6-C
10) aryl, (C
6-C
10) aryloxy, (C
5-C
9) heteroaryl, (C
5-C
9) heteroaryl oxygen base, morpholino-carbonyl, (C
1-C
6) alkoxy amino carbonyl, (C
1-C
6) alkyl-carbonylamino, (C
3-C
8) cycloalkyl, (C
3-C
8) cycloalkyl-methyl, (C
3-C
8) Heterocyclylalkyl, (C
3-C
8) Heterocyclylalkyl-methyl.
In a certain embodiment, the present invention includes the compound of one group of belt (I) structure, be called Compound I A2, the chemical formula of wherein said compound is as follows:
Wherein R
16, R
17and R
18respectively hydrogen, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl; Key in the middle of carbon a and b or d and e may be singly-bound or two key.R
5, R
6, R
7, R
9, R
10, R
11, R
12, R
13with the definition of X as previously mentioned.
In a certain embodiment, the present invention includes the compound of one group of belt (I) structure, be called Compound I A3, the chemical formula of wherein said compound is as follows:
Wherein R
16, R
17, R
18and R
20respectively hydrogen, (C
1-C
6) alkyl; R
9, R
10, R
11, R
12, R
13respectively hydrogen, (C
1-C
6) alkyl; X is H, OR
1or NR
2r
3, R
1, R
2and R
3respectively hydrogen, (C
1-C
6) alkyl or R
2r
3common Wei – (CH
2)
n–, n=2 to 8; Key in the middle of carbon a and b or d and e may be singly-bound or two key.R
5and R
6definition as previously mentioned.
In a certain embodiment, the present invention includes the compound of one group of belt (I) structure, be called Compound I A4, the chemical formula of wherein said compound is as follows:
Wherein R
16, R
17, R
18, R
19and R
20respectively hydrogen, (C
1-C
6) alkyl; X is OR
1or NR
2r
3, R
1, R
2and R
3respectively hydrogen, (C
1-C
6) alkyl or R
2r
3common Wei – (CH
2)
n–, n=2 to 5;
In a certain embodiment, the present invention includes the compound of one group of belt (I) structure, be called Compound I A5, the chemical formula of wherein said compound is as follows:
Wherein R
16, R
17, R
18, R
19and R
20respectively hydrogen, (C
1-C
6) alkyl; X is OR
1or NR
2r
3, R
1, R
2and R
3respectively hydrogen, (C
1-C
6) alkyl or R
2r
3common Wei – (CH
2)
n–, n=2 to 5;
In a certain embodiment, the present invention includes the compound of one group of belt (I) structure, be called Compound I A6, the chemical formula of wherein said compound is as follows:
Wherein R
16, R
17, R
18, R
19and R
20respectively hydrogen, (C
1-C
6) alkyl; X is OH or NH
2.
The compound of preferred belt (I) structure includes but not limited to following listed compound:
8-(3-amino-3-methyl butyl)-3,5,7-trihydroxy--2-(4-hydroxy phenyl)-4H-benzopyran-4-one
8-(3-amino-3-methyl butyl)-3,5,7-trihydroxy--2-(4-p-methoxy-phenyl)-4H-benzopyran-4-one
8-(3-amino-3-methyl butyl)-5,7-dihydroxyl-3-methoxyl group-2-(4-p-methoxy-phenyl)-4H-benzopyran-4-one
5,7-dihydroxyl-8-(3-hydroxy-3-methyl butyl)-3-methoxyl group-2-(4-p-methoxy-phenyl)-4H-benzopyran-4-one
5,7-dihydroxyl-8-(3-hydroxy-3-methyl butyl)-3-methoxyl group-2-(3,4-Dimethoxyphenyl)-4H-benzopyran-4-one
5-hydroxyl-8-(3-hydroxy-3-methyl butyl)-3,7-dimethoxy-2-(3,4-Dimethoxyphenyl)-4H-benzopyran-4-one
8-(3-amino-3-methyl butyl)-5-hydroxyl-3,7-dimethoxy-2-(3,4-Dimethoxyphenyl)-4H-benzopyran-4-one
3-(2-(piperidin-1-yl) oxyethyl group)-5,7-dihydroxyl-8-(3-hydroxy-3-methyl butyl)-2-(4-p-methoxy-phenyl)-4H-benzopyran-4-one
3-(2-(piperidin-1-yl) oxyethyl group)-8-(3-amino-3-methyl butyl)-5,7-dihydroxyl-2-(4-p-methoxy-phenyl)-4H-benzopyran-4-one
2-(4-chloro-phenyl-)-3,5,7-trihydroxy--8-(3-hydroxy-3-methyl butyl)-4H-benzopyran-4-one
2-(the chloro-3-p-methoxy-phenyl of 4-)-3,5,7-trihydroxy--8-(3-hydroxy-3-methyl butyl)-4H-benzopyran-4-one
8-(3-amino-3-methyl butyl)-3,5,7-trihydroxy--2-(pyridin-3-yl)-4H-benzopyran-4-one
8-(3-amino-3-methyl butyl)-3,5,7-trihydroxy--2-(pyridine-2-yl)-4H-benzopyran-4-one
8-(3-amino-3-methyl butyl)-5,7-dihydroxyl-3-methoxyl group-2-(5-methoxypyridine-2-yl)-4H-benzopyran-4-one
5,7-dihydroxyl-8-(3-hydroxy-3-methyl butyl)-3-methoxyl group-2-(6-methoxypyridine-3-yl)-4H-benzopyran-4-one
5,7-dihydroxyl-3-methoxyl group-8-(3-methyl but-2-ene base)-2-(pyridin-3-yl)-4H-benzopyran-4-one
2-(6-(dimethylamino) pyridin-3-yl)-5,7-dihydroxyl-3-methoxyl group-8-(3-methyl but-2-ene base)-4H-benzopyran-4-one
2,3-dihydro-5,7-dihydroxy-2-(4-p-methoxy-phenyl)-8-(3-methyl but-2-ene base) quinoline-4 (1H)-one
2,3-dihydro-7-hydroxyl-2-(4-p-methoxy-phenyl)-8-(3-methyl but-2-ene base) quinoline-4 (1H)-one
7-hydroxyl-2-(4-p-methoxy-phenyl)-8-(3-methyl but-2-ene base) quinoline-4 (1H)-one
5,7-dihydroxyl-2-(4-p-methoxy-phenyl)-8-(3-methyl but-2-ene base) quinoline-4 (1H)-one
8-(3-amino-3-methyl butyl)-5,7-dihydroxyl-2-(4-hydroxy phenyl)-4H-benzopyran-4-one
8-(3-amino-3-methyl butyl)-5,7-dihydroxyl-2-(4-p-methoxy-phenyl)-4H-benzopyran-4-one
8-(3-amino-3-methyl butyl)-2,3-dihydro-5,7-dihydroxyl-2-(4-p-methoxy-phenyl) benzopyran-4-one
5,7-dihydroxyl-8-(3-hydroxy-3-methyl butyl)-2-(4-p-methoxy-phenyl)-4H-benzopyran-4-one
5,7-dihydroxyl-8-(3-hydroxy-3-methyl butyl)-2-(3,4-Dimethoxyphenyl)-4H-benzopyran-4-one
5-hydroxyl-8-(3-hydroxy-3-methyl butyl)-7-methoxyl group-2-(3,4-Dimethoxyphenyl)-4H-benzopyran-4-one
8-(3-amino-3-methyl butyl)-5-hydroxyl-7-methoxyl group-2-(3,4-Dimethoxyphenyl)-4H-benzopyran-4-one
2,3-dihydro-5,7-dihydroxyl-8-(3-hydroxy-3-methyl butyl)-2-(4-p-methoxy-phenyl) benzopyran-4-one
2-(4-aminophenyl)-5,7-dihydroxyl-8-(3-hydroxy-3-methyl butyl)-4H-benzopyran-4-one
2-(4-chloro-phenyl-)-5,7-dihydroxyl-8-(3-hydroxy-3-methyl butyl)-4H-benzopyran-4-one
2-(the chloro-3-p-methoxy-phenyl of 4-)-5,7-dihydroxyl-8-(3-hydroxy-3-methyl butyl)-4H-benzopyran-4-one
2-(4-aminophenyl)-2,3-dihydro-5,7-dihydroxyl-8-(3-hydroxy-3-methyl butyl) benzopyran-4-one
2-(4-chloro-phenyl-)-2,3-dihydro-5,7-dihydroxyl-8-(3-hydroxy-3-methyl butyl) benzopyran-4-one
2-(the chloro-3-p-methoxy-phenyl of 4-)-2,3-dihydro-5,7-dihydroxyl-8-(3-hydroxy-3-methyl butyl) benzopyran-4-one
7-hydroxyl-8-(3-methyl but-2-ene base)-2-(pyridin-4-yl)-4H-benzopyran-4-one
7-hydroxyl-8-(3-methyl but-2-ene base)-2-(pyridin-3-yl)-4H-benzopyran-4-one
The application's compound and derivative thereof are to name according to IUPAC (International Union of Pure and Applied Chemistry(IUPAC)) or CAS (chemical abstracts service is positioned at Columbus city, Ohio) naming system.
In hydrocarbon group, the minimum value of carbon content and maximum value are passed through prefix designates, for example, and prefix (C
a-C
b) alkyl represent any containing " a " to alkyl of " b " individual carbon atom.Therefore, for example, (C
1-C
6) alkyl refers to and comprise an alkyl to six carbon atom.
" alkoxyl group " refers to the straight chain of a Sauerstoffatom bonding or with side chain, unit price, saturated aliphatic chain, includes but not limited to as methoxyl group, oxyethyl group, propoxy-, butoxy, isobutoxy, tert.-butoxy and other similar group.
" alkyl " refers to straight chain or with side chain, unit price, saturated aliphatic chain, includes but not limited to as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, amyl group, isopentyl, hexyl and other similar group.
" thiazolinyl " refers to the straight or branched hydrocarbon with one or more pairs of keys, includes but not limited to as vinyl, propenyl and other similar group.
" aryl " refers to a kind of aromatic hydrocarbon of ring-type, includes but not limited to as phenyl, naphthyl, anthryl, phenanthryl and other similar group.
" cycloalkyl " refers to saturated monocycle or multi-ring alkyl, may condense with an aromatic hydrocarbon group.Cycloalkyl includes but not limited to as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, indanyl, tetrahydro naphthyl and other similar group.
" halogen " refers to chlorine, bromine, fluorine and iodine atom or group.
" heteroaryl " refers to monocycle or polynuclear aromatics, and one or more carbon atom is replaced as heteroatomss such as nitrogen, oxygen or sulphur.If heteroaryl contains a more than heteroatoms, these heteroatomss may be identical, may be also different.Heteroaryl includes but not limited to as benzofuryl, benzothienyl, benzimidazolyl-, benzoxazolyl, benzothiazolyl, benzopyranyl, furyl, imidazolyl, indazolyl, indolizine base, indyl, isobenzofuran-base, pseudoindoyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazinyl, oxazolyl, phthalazinyl, pteridyl, purine radicals, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridine [3, 4-b] indyl, pyridyl, pyrimidyl, pyrryl, quinolizinyl, quinolyl, quinoxalinyl, thiadiazolyl group, thiatriazole base, thiazolyl, thienyl, triazinyl, triazolyl, xanthenyl and other similar group.
" Heterocyclylalkyl " refers to saturated monocycle or multi-ring alkyl, may condense with an aromatic hydrocarbon group, wherein has at least a carbon atom to be got and replace as heteroatomss such as nitrogen, oxygen or sulphur.If Heterocyclylalkyl contains a more than heteroatoms, these heteroatomss may be identical, may be also different.Heterocyclylalkyl includes but not limited to as azabicyclic heptane base, azetidinyl, indolinyl, morpholinyl, piperazinyl, piperidyl, pyrrolidyl, tetrahydrofuran base, tetrahydric quinoline group, tetrahydrochysene indazole base, tetrahydro indole base, tetrahydro isoquinolyl, THP trtrahydropyranyl, tetrahydroquinoxaline base, tetrahydro thiapyran base, thiazolidyl, thio-morpholinyl, thioxanthene base, thiophene oxane base and other similar group.
Cyclic group can be in several ways and another group bonding.If not clear and definite bonding mode, represents to comprise all possible mode.For example, " pyridyl " comprises 2-, 3-or 4-pyridyl, and " thienyl " comprises 2-or 3-thienyl.
" oxo " refer to be combined with one (many) individual Sauerstoffatoms by one (many) individual carbon atoms form carbonyl.
" prodrug " refers to a kind of compound as prodrug, and this compound can be after to main body administration for example, discharges active medicine by a chemistry or physiological process (, by be placed in physiological pH value or by enzyme effect) in vivo.About the synthetic discussion with using of prodrug, article referring to T.Higuchi and W.Stella is entitled as " Prodrugs as Novel DeliverySystems ", the 14th phase of the ACS Symposium Series, also has the article of ed.Edward B.Roche: Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, the content of these two sections of articles is all cited and is incorporated herein." prodrug " also can comprise the metabolic precursor thereof of the compounds of this invention, and such prodrug may not have activity when to main body administration, but can be converted in vivo compound of the present invention.Prodrug can be the compound of nature existence or synthetic compound.
" pharmaceutically useful " refer to certain carrier, load, thinner, auxiliary material and/or salt conventionally chemically or physically with form certain pharmaceutical dosage form other becomes phase-splitting compatibility, and on physiology with acceptor compatibility mutually.
" salt " and " pharmaceutically useful salt " refers to the compound shown in formula (I), or its steric isomer, or the organic salt of its prodrug and inorganic salt.These salt can be in the time that compound separation be purified immediate system standby, or by use suitable organic or inorganic acid or alkali respectively with compound shown in formula (I), or its steric isomer, or its prodrug reaction, then separate and obtain salt.Conventional salt comprise hydrobromate, hydrochloride, vitriol, hydrosulfate, nitrate, acetate, oxalate, benzene sulfonate, palmitate, stearate, lauroleate, borate, benzoate, lactic acid salt, phosphoric acid salt, tosylate, Citrate trianion, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, gluceptate, Lactobionate and dodecane sulfonate and other class saloid.These salt may also comprise the positively charged ion in alkali or alkaline-earth metal, for example sodium, lithium, potassium, calcium, magnesium and other analogue, and nontoxic ammonium, quaternary ammonium and ammonium cation, include but not limited to ammonium, tetramethyl-ammonium, Tetrylammonium, methylamine, dimethylamine, Trimethylamine 99, triethylamine, ethamine and other analogue.Other example please see as J.Pharm.Sci. that people write such as Berge,
66, 1-19 (1977), the content of the document is cited into herein.
The salt of compound shown in formula (I) can be by suitably mixing compound solution shown in formula (I) to make with needed acid or alkali.Salt may form precipitation in solution, can collect by filtration, or reclaim after solvent evaporation.
" replacement " refers to that the hydrogen atom on molecule replaced by other different atom or molecule.Atom or the molecule of replacing hydrogen atom are called as " substituting group ".
The compound of formula (I) may be because comprising asymmetric structure or with chirality, and exist with different stereoisomeric forms in any ratio.Steric isomer of compound and composition thereof shown in all formulas (I), comprises that racemic mixture all belongs to a part of the present invention.In addition, also comprise all geometrical isomers and positional isomers.For example, if compound is with two keys shown in formula (I), be included in scope of the present invention with cis and trans compound existing and composition thereof so.
The method that the mixture of diastereomer can be known by those of ordinary skill in the art, is isolated according to the difference on diastereomer physics and chemistry, for example chromatography and/or Steppecd crystallization.Enantiomer can be by for example, reacting enantiomeric mixture to change into non-enantiomer mixture with suitable activity of optically active compounds (alcohols), isolate diastereomer, and for example, be corresponding pure enantiomer by each diastereomer conversion (hydrolysis).Meanwhile, some compounds of formula (I) may be atropisomer (dibenzyl for example replacing), and these also should serve as a part of the present invention.
Compound shown in formula (I) can non-solvent form exist, also can acceptable solvent form exist, and for example water, ethanol and analogue, the present invention should comprise solvent and non-solvent form.
Compound shown in formula (I) also may keep equilibrium state with the form of tautomer, and all these forms should be within the scope of the present invention.
In certain embodiments, the invention provides isotope-labeled formula (I) compound, it is consistent with those compounds described here, but one or more atom is replaced by another atom, the atomic mass of this atom or total mass number are different from atomic mass common in the Nature or total mass number.Can be included into isotropic substance in formula (I) compound comprise as the isotropic substance of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine as
2h,
3h,
13c,
14c,
15n,
17o,
18o,
31p,
32p,
35s,
18f and
36cl.Formula (I) compound, steric isomer or its prodrug that contain aforementioned isotropic substance and/or other atom isotope, and the pharmaceutically useful salt of this compound, steric isomer or prodrug all should be within the scope of the present invention.
Some isotope-labeled compound shown in formula (I), for example those by as
3h and
14the compound of the labelled with radioisotope such as C, can be in compound and/or the analysis of substrate tissue distribution.Owing to containing tritium being
3the isotropic substance of H and carbon-14 are
14the relatively easy preparation of C isotropic substance and detection, we are preferred
3the isotropic substance of H and
14c isotropic substance.In addition, some heavier isotropic substance as deuterium is
2h has metabolic stability, uses this coordination usually to replace and may have some treatment advantage, for example, is increased in the transformation period in live body or reduces dosage, therefore in some cases can first-selected such isotropic substance.The method preparation that isotope-labeled formula (I) compound can use those of ordinary skill in the art to know, for example, replace a heterotope labelled reagent with an isotope labeling reagent.
Using method
In certain embodiments, compound of the present invention is the setter of ER-α 36, for regulating ER-α 36 function of cell in vitro and in vivo.This group compound is also for preventing and/or treating the disease relevant to the function of ER-α 36 or dysfunction.In certain embodiments, compound of the present invention can inducing cell death and/or is suppressed cell proliferation, therefore can be used for preventing and/or treating the disease of cells involved abnormality proliferation.In certain embodiments, compound of the present invention is used for preventing and/or treating osteoporosis, asthma and other respiratory tract disease.
In certain embodiments, the invention provides the method that regulates the function of ER-α 36 in cell, the method comprises formula (I) compound effects in the cell of an expression ER-α 36.ER-α 36 can be by cell endogenous expression or by the ectogenic expression of gene engineering method.In a certain embodiment, the endogenic expression of cell ER-α 36.In a preferred embodiment, endogenous expression ER-α's 36 is cancer cells.The cancer cells of expressing ER-α 36 includes but not limited to as breast cancer cell, leukemia cell, lung carcinoma cell, myeloma cell, prostate cancer cell, ovarian cancer cell, colon cancer cell and stomach cancer cell.In a preferred embodiment, the cell of expressing ER-α 36 is breast cancer cells of endogenous expression ER-α 36.The breast cancer cell of expressing ER-α 36 comprises as MCF7 and MDA-MB-231 cell.The expression of endogenous ER-α 36 can be processed and be increased or reduce by one or more conditioning agents.These conditioning agents comprise as serum, E2 (17-estradiol), tamoxifen and ICI182,780.
In another embodiment, changing a cell by gene engineering method makes it express exogenous ER-α 36.Expressing the gene engineering method that the cell of exogenous ER-α 36 can know by those of ordinary skill in the art prepares (referring to people such as Sambrook, Molecular Cloning, A Laboratory Manual (2d Ed.1989) (Cold Spring HarborLaboratory)).Concise and to the point, first prepare exogenous ER-α 36 genes, be inserted into an expression vector, then by expression vector transfection to host cell, then host cell is put into the nutrient solution that is applicable to expressing exogenous ER-α 36 and is grown.Following article has disclosed the gene order of a mankind ER-α 36: the people such as Wang, Biochem.Biophys.Res.Commun.336,1023-1027 (2005) (GenBank Accession No.BX640939).The cell of expressing exogenous ER-α 36 also may be with endogenous ER-α 36, also may be without endogenous ER-α 36.Endogenous or the expression amount of exogenous ER-α 36 in cell may increase or reduce after using one or more conditioning agents to process.These reagent comprise as serum, E2 β (17 beta estradiol), tamoxifen and ICI182,780.
The cell of expression ER-α 36 may be expressed and also may do not expressed other estrogen receptor, as ER-α 66, and ER-α 46 and ER-β.
In certain embodiments, the invention provides the method that prevents and/or treats the disease being mediated by ER-α 36 in a main body, the method comprises carries out administration to main body with the pharmaceutical composition that one contains compound shown in formula (I).The disease being mediated by ER-α 36 includes but not limited to senile dementia, nerve degeneration, neural aging and damage, birth control, miscarriage, bone-loss, fracture, osteoporosis, pernicious bone diseases, Paget's disease, periodontopathy, cartilage degradation, endometriosis, hysteromyoma, hot flush, increasing of LDL-C, cardiovascular disorder, cognition dysfunction, brain degenerated confusion, restenosis, gynecomastia, vascular smooth muscle cell proliferation, fat, incontinence, anxiety, the melancholy that oestrogen deficiencies causes, melancholy in climacteric, Maternity blues, premenstrual syndrome, manic depressions, dull-witted, obsession, attention deficit syndrome, insomnia, easily hot-tempered, inflammable, immune deficiency, autoimmune disease, indignation is controlled training, multiple sclerosis and Parkinson's disease, inflammation, inflammatory bowel, respiratory tract disease, sexual dysfunction, hypertension, retinal degeneration, asthma and cancer.Preferably, the disease being mediated by ER-α 36 comprises that bone-loss, fracture, osteoporosis, menopause, premenstrual syndrome, endometriosis, hysteropathy, impotence, sexual dysfunction, LDL-C increase, cardiovascular disorder, vascular smooth muscle cell proliferation, oestrogen deficiencies cause melancholy, melancholy in climacteric, Maternity blues, immune deficiency, autoimmune disease, inflammation, asthma and cancer.Preferred, the disease being mediated by ER-α 36 comprises bone-loss, osteoporosis, impotence, cardiovascular disorder, immune deficiency, inflammation, asthma and cancer.Main body can be arbitrary Mammals as dog, cat, ox, sheep, horse or people, be preferably people.The required therapeutic dose of methods for the treatment of changes because of the difference of disease specific, and according to the present invention, content can be easy to just determine associated treatment amount to those of ordinary skill in the art.
In certain embodiments, the invention provides the method for inducing cell death, the method comprises the formula of significant quantity (I) compound effects in cell.In addition, some embodiment of the present invention provides the method that suppresses cell proliferation, comprises the formula of significant quantity (I) compound effects in cell.The growth of cell may be normal or abnormal.Abnormal cell growth may be optimum or pernicious.In a certain embodiment, the cell being applied is cancer cells.In a preferred embodiment, cancer cells comes from anus cancer, cholangiocarcinoma, bladder cancer, osteocarcinoma, intestinal cancer (colorectal carcinoma, the rectum cancer), the cancer of the brain, mammary cancer, carcinoid, cervical cancer, internal secretion associated cancer, carcinoma of endometrium, cancer eye, carcinoma of gallbladder, head and neck cancer, Kaposi sarcoma cancer, kidney, laryngocarcinoma, leukemia, liver cancer, lung cancer, lymphoma cancer, melanoma cancer, mesothelioma cancer, myelomatosis cancer, neuroendocrine carcinoma, esophagus cancer, ovarian cancer, carcinoma of the pancreas, penile cancer, prostate cancer, skin carcinoma, soft tissue sarcoma's cancer, spinal cord cancer, cancer of the stomach, carcinoma of testis, thyroid carcinoma, carcinoma of vagina, carcinoma vulvae or uterus carcinoma.Preferably, cancer cells comes from mammary cancer, cervical cancer, colorectal carcinoma, carcinoma of endometrium, leukemia, liver cancer, lung cancer, myelomatosis, ovarian cancer, prostate cancer, cancer of the stomach or uterus carcinoma.Preferably, cancer cells comes from mammary cancer, cervical cancer, carcinoma of endometrium, lung cancer, uterus carcinoma or prostate cancer.In certain embodiments, cell can endogenous or exogenous expression's estrogen receptor, particularly ER-α 36.In a more preferred embodiment, cell can endogenous expression ER-α 36.
The significant quantity that is used for formula (I) compound of inducing cell death and/or inhibition cell proliferation changes along with the difference of concrete cell type and treatment situation.The content that those of ordinary skill in the art disclose according to the application can be easy to determine relevant significant quantity.In a certain embodiment, the effective concentration that acts on formula (I) compound of cell is at least about 0.1 μ M.In another embodiment, the concentration of formula (I) compound that acts on cell is between 0.1 μ M to 100 μ M.Preferred, the effective concentration of compound is about between 5 μ M to 50 μ M or about between 5 μ M to 30 μ M or about between 5 μ M to 25 μ M or about between 5 μ M to 20 μ M or between 5 μ M to 10 μ M.
In certain embodiments, the invention provides the disease method that in a main body, abnormal cell proliferation is relevant that prevents and/or treats, the method comprises that the pharmaceutical composition that contains compound shown in formula (I) with dose therapeutically effective is to being treated main body administration.
Abnormal cell proliferation may be optimum Growth of Cells or cancerous swelling.In one embodiment, the disease of cells involved abnormality proliferation is cancer.Preferably, this cancer is anus cancer, cholangiocarcinoma, bladder cancer, osteocarcinoma, intestinal cancer (colorectal carcinoma, the rectum cancer), the cancer of the brain, mammary cancer, carcinoid, cervical cancer, internal secretion reaction cancer, carcinoma of endometrium, cancer eye, carcinoma of gallbladder, head and neck cancer, Kaposi sarcoma cancer, kidney, laryngocarcinoma, leukemia cancer, liver cancer, lung cancer, lymphoma cancer, melanoma cancer, mesothelioma cancer, myelomatosis cancer, neuroendocrine carcinoma, esophagus cancer, ovarian cancer, carcinoma of the pancreas, penile cancer, prostate cancer, skin carcinoma, soft tissue sarcoma's cancer, spinal cord cancer, cancer of the stomach, carcinoma of testis, thyroid carcinoma, carcinoma of vagina, carcinoma vulvae or uterus carcinoma.Preferred, this cancer is mammary cancer, cervical cancer, colorectal carcinoma, carcinoma of endometrium, leukemia, liver cancer, lung cancer, myelomatosis, ovarian cancer, prostate cancer, cancer of the stomach or uterus carcinoma.Preferably, this cancer is mammary cancer, cervical cancer, carcinoma of endometrium, lung cancer, uterus carcinoma or prostate cancer.
In certain embodiments, the invention provides the method that prevents and/or treats asthma or other respiratory tract disease in a main body, comprise that the pharmaceutical composition that contains compound shown in formula (I) with dose therapeutically effective is to being treated main body administration.Asthma comprises the air flue inflammatory diseases of all reversible obstruction of the air passage.Other respiratory tract disease comprises respiratory tract and pulmonary disorder, for example bronchitis, cystic fibrosis disease, pulmonary emphysema, pneumonia, rheum and sinusitis paranasal sinusitis.
Be treated preferably Mammals of main body.In a certain embodiment, Mammals is dog, cat, ox, sheep, horse or people.Mammals is preferably people.
Compound shown in formula (I) can be by any method that compound can be passed to site of action to being treated main body administration.These methods include but not limited to by such as, such as, in oral cavity, mucous membrane, hypogloeeis, eyes, part (skin), enteron aisle outer (vein, muscle, subcutaneous, blood vessel or every closing), rectum, brain pond, the position administration such as vagina, peritonaeum, bladder or nasal cavity.
The compound of formula (I) to dosage every day of a main body administration at about 0.1mg to approximately 3, between 000mg, be preferably every day at about 0.1mg to approximately 1, between 000mg, or every day at about 1mg between about 500mg, or every day at about 1mg between about 300mg, or every day at about 10mg between about 300mg, or every day at about 10mg between about 200mg, or every day at about 20mg between about 200mg, or every day at about 30mg between about 200mg, or every day about 40mg between about 200mg, or every day about 50mg between about 200mg, or every day at about 50mg between about 100mg.Concerning an individual weight is about the normal adult human of 70kg, the common per kilogram of dosage (Kg) body weight giving is extremely just enough between about 100mg at about 0.01mg, more preferably per kilogram of body weight at about 0.1mg between about 100mg, or per kilogram of body weight at about 0.5mg between about 100mg, or per kilogram of body weight at about 1mg between about 100mg, or per kilogram of body weight at about 1mg between about 75mg, or per kilogram of body weight at about 1mg between about 50mg, or per kilogram of body weight at about 1mg between about 25mg, or per kilogram of body weight at about 1mg between about 10mg, or per kilogram of body weight at about 2mg between about 5mg.But, different according to the age that is treated main body and body weight, the difference of route of administration, and the singularity of the compound of giving and other analogue, the dosage of medication can change to some extent in general dosage range.Those of ordinary skill in the art can determine dosage range and the optimal dose to the medication of a certain mammals main body on the application basis.
In certain embodiments, one or more compound of the present invention can be used in combination mutually.Also can select compound of the present invention to be combined with any other active agent, for regulating cell function or treatment disease.If what use is one group of compound, can be by these compounds simultaneously, respectively or in an orderly manner main body be carried out to administration.
In certain embodiments, compound of the present invention can be combined with one or more other antitumor and anticancer agents.Available antitumor and anticancer agent includes but not limited to alkylating agent, chlormethine series pharmaceuticals, antifol, purine antagonist, pyrimidine antagonist, spindle poison, Topoisomerase inhibitors, apoptosis induction reagent, revascularization inhibitor, podophyllotoxin, nitrosourea, metabolic antagonist, protein synthesis inhibitor, kinase inhibitor, antiestrogen, Platinol, NSC-241240, Interferon, rabbit, arginase, Leuprolide, flutamide, megestrol, mitomycin, bleomycin, adriamycin, Rinotecan and taxol.In a certain embodiment, antitumor and anticancer agent is antiestrogen, for example tamoxifen and ICI182,780.
The ability that uses the reconstitution cell of expressing exogenous ER-α 36 can test compound inducing cell death of the present invention or inhibition cell proliferation.For preparing reconstitution cell, first prepare exogenous ER-α 36 genes, be inserted in an expression vector, more do not express or express the host cell of little endogenous ER-α 36 with expression vector transfection, then select the reconstitution cell as test analysis by the host cell of stable transfection.Part reconstitution cell is cultivated together with the compounds of this invention, and another part is not cultivated with the compounds of this invention.The relatively cell quantity under survival after use compound of the present invention is treated and do not used compound of the present invention to treat.When the cell quantity (on statistical significance) of survival after test compound treatment lower than after not using test compound, survive cell quantity time, show that test compound can inducing cell death and/or suppress cell proliferation.
Above-mentioned reconstitution cell also can be used for testing the ability of compound adjusting ER-α of the present invention 36 functions.Under equal conditions, with test compound to expressing the reconstitution cell of exogenous ER-α 36 and not transfected host cell is treated.The method observable that use those of ordinary skill in the art know the function of analyzing ER-α 36, these functions include but not limited to that ER-α 36 activates the ability of its downstream signal Signal Transduction Pathways, for example, activate the ability of mitogen activated protein kinase (the MAPK/ERK) path or Jun N terminal kinase (JNKs) path.
Pharmaceutical composition
In certain embodiments, compound shown in formula (I), its steric isomer or its prodrug, or the pharmaceutically useful salt of the one of this compound, steric isomer or prodrug, can, with the form administration of pharmaceutical composition, wherein comprise pharmaceutically useful carrier, load or thinner.Correspondingly, compound, its steric isomer or its prodrug shown in formula (I), or the pharmaceutically useful salt of the one of this compound, steric isomer or prodrug, can be any conventional formulation form respectively or jointly to main body administration, that conventional administering mode comprises is outer by oral cavity, mucous membrane, hypogloeeis, eyes, Pi Shang, enteron aisle, in rectum, brain pond, vagina, peritonaeum, bladder, local (as medicinal powder, ointment, drops) or nasal administration.
Be suitable for parenteral introduction and comprise pharmaceutically useful sterilized water or non-aqueous solution, dispersion liquid, suspension or emulsion for the pharmaceutical composition of injecting, and quickly dissolving in the aseptic powder of aseptic injectable solution or dispersion liquid.Applicable water or nonaqueous carrier, load and thinner comprise as water, ethanol, polyvalent alcohol (as propylene glycol, polyoxyethylene glycol, glycerol and analogue) and suitable mixture thereof, the organosilane ester that vegetables oil (as sweet oil) and injectable are used, as ethyl oleate.Can maintain the suitable mobility of medicine by some method, for example, by using as tectums such as Yelkin TTS, by maintaining granular size required in dispersion liquid, and by using the method for tensio-active agent.
In certain embodiments, pharmaceutical composition of the present invention may further include auxiliary material, for example preservation agent, wetting agent, emulsifying agent and dispersion agent.Can utilize different antiseptic-germicides and anti-mycotic agent to prevent said composition to produce microorganism, for example metagin, butylene-chlorohydrin, phenol, Sorbic Acid and analogue.Pharmaceutical composition of the present invention also can comprise isotonic agent, for example sugar, sodium-chlor and analogue.If need the soak time of prolong drug composition, can use the assistant agent that can postpone absorption, such as aluminum monostearate and gel etc.
Solid orally ingestible comprises capsule, tablet, medicinal powder and powder.In certain embodiments, active compound at least with a kind of inert pharmaceutical vehicle (or carrier) phase fusion of routine, for example Trisodium Citrate or Si Liaodengji dicalcium phosphate feed grade, or (a) weighting agent or additive, for example starch, lactose, sucrose, N.F,USP MANNITOL or silicic acid; (b) tackiness agent, for example carboxymethyl cellulose, alginates, gel, polyvinylpyrrolidone, sucrose or Sudan Gum-arabic; (c) wetting Agent for Printing Inks, for example glycerol; (d) disintegrating preparations, for example agar, calcium carbonate, potato or tapioca (flour), alginic acid, some composition silicate or sodium carbonate; (e) solution retardant, for example paraffin; (f) accelerate absorption agent, for example quaternary ammonium compound; (g) wetting agent, for example cetyl alcohol or glyceryl monostearate; (h) sorbent material, for example kaolin or bentonite; And/or (i) lubricant, for example talcum, calcium stearate, Magnesium Stearate, solid polyethylene glycol, osmanthus sodium sulfovinate or its mixture.With regard to capsule and tablet, preparation may further contain buffer reagent.
In certain embodiments, solid preparation can be prepared to the adjusting release preparation and the pulsed release preparation that contain vehicle, these vehicle comprise that these are all painted on medicine or put into medicine as above vehicle and other vehicle as rate of release instrumentality that directly release preparation can be used.Rate of release instrumentality includes but not limited to, Vltra tears. methylcellulose gum, Xylo-Mucine, ethyl cellulose, cellulose acetate, polyethylene oxide, xanthan gum, ammonio methacrylate copolymer, hydrogenated castor oil, carnauba wax, solid paraffin, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, Sipacril 2739OF and composition thereof.Regulate release preparation and pulsed release preparation can comprise one or more rates of release and regulate vehicle.
In certain embodiments, pharmaceutical composition of the present invention can further comprise the rapid dispersion that contains following composition or dissolve preparation (FDDFs): aspartame, acesulfame, citric acid, croscarmellose sodium, Crospovidone, two xitix (diascorbic acid), ethyl propenoate, ethyl cellulose, gel, Vltra tears, Magnesium Stearate, N.F,USP MANNITOL, methyl methacrylate, mint flavouring, polyoxyethylene glycol, fumed silica, silicon-dioxide, sodium starch glycollate, sodium stearyl fumarate, sorbyl alcohol, Xylitol.Being used herein to and describing the word " dispersion " of FDDFs or " dissolving " is solubleness based on used medicine, and, in the time that medicine can not dissolve, what can prepare is rapid dispersion preparation, and in the time of medicine solubilized, preparation be to dissolve fast preparation.
In using as the soft or hard capsule of the vehicle such as lactose or toffee and high molecular weight polyethylene glycol and analogue, the solids composition of similar type also can be used as weighting material.
In certain embodiments, the solid preparations such as tablet, drageeing, capsule and powder can be with dressing and shell, and this type of dressing and shell can comprise the material that enteric coating and other those of ordinary skill in the art know.Solid preparation also can comprise opacifying agent or can be with slowly-releasing, that continue, the mode release of active compounds that has control.The material that can be used for embedding comprises as polymer and wax etc.If needed, active compound also can be prepared to micro-capsule together with one or more aforesaid vehicle.
In certain embodiments, liquid oral medicine comprises pharmaceutically useful emulsion, solution, suspension, syrup and elixir.Except active compound, liquid preparation also can comprise the inert diluent that this area is conventional, as water or other solvent, chaotropic agent and/or emulsifying agent, as ethanol, Virahol, ethyl-carbonate, peruscabin, propylene glycol, 1,3-butyleneglycol, the particularly fatty acid ester of cottonseed oil, peanut oil, Fructus Maydis oil, sweet oil, Viscotrol C or sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyoxyethylene glycol or sorbitanic of oil, the mixture of these materials, and other similar material.
Except these inert diluents, pharmaceutical composition also can comprise auxiliary material, for example wetting agent, emulsifying agent and suspension agent, sweeting agent, odorant and perfume compound.Pharmaceutical composition can further comprise suspension agent, for example ethoxylation i-octadecanol, polyoxyethylene sorbitol and sorbitan ester, Microcrystalline Cellulose, hydroxide metal aluminium (aluminum metahydroxide), bentonite, agar and tragacanth, the mixture of these materials, and other similar substance.
In certain embodiments, pharmaceutical composition of the present invention also can be used for treating Animal diseases.Animal doctor can be for animals by a kind of compound of the present invention or its according to working experience salt, or solvent that can be for animals or its prodrug are with suitable acceptable dosage form administration.Animal doctor can determine the optimal dosage of a certain animal and route of administration.
If by the administration of getting up of various active compound combination, these active compounds can be by simultaneously, respectively or with a definite sequence administration.
The compound of formula (I) can be prepared by different synthetic methods.Typical preparation process is listed as follows.Unless had other to represent, R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, R
11, R
12, R
13, R
14, R
15, R
16, R
17, R
18, R
19, R
20,
the definition of X and Y as previously mentioned.P represents a blocking group.In the reactions steps of the following stated; can protect NH or hydroxyl according to known method; slough again blocking group; this currently known methods is as the method for the people such as T.W.Greene described in the Protective Groups in Organic Synthesis (John Wiley & Sons, 1991).Generally independent hydroxyl groups can be transformed into ether, acetal and ester protects.As a rule, phenyl class blocking group can be removed by hydrogenolysis.Silyl ether can be by reacting with fluorion or sloughing under slightly acidic condition.Several 2-replace ether can pass through the removal of β-elimination reaction.Should be appreciated that, the following several specific exampless that provide are provided in the present invention.In following discussion, used chemically with program on some common abbreviation or write a Chinese character in simplified form, comprising: Me (methyl); Et (ethyl); EtOAc (ethyl acetate); Bn (phenmethyl); THF (tetrahydrofuran (THF)); DMF (dimethyl formamide); Boc (tertbutyloxycarbonyl); DMAP (1,1 '-Dimethylamino pyridine); DIBAL (diisobutyl aluminium hydride); Eq (equivalent); RP (anti-phase); HPLC (high performance liquid chromatography); TLC (thin layer chromatography), MOM (methoxymethyl); The synthetic method of formula (I) compound most convenient may be the similarity method of the known production similar compound in this field.As further feature of the present invention, the production method of formula described above (I) compound, will further be set forth by the following example, and such production method is also a part of the present invention.Listed embodiment 1,2,3 and 4 and associated description, only as some example of the preparation method of the compounds of this invention, not limit the scope of the invention below.
Brief description of the drawings
Fig. 1 is antibody labeling (Westernblot) detected result that ER-α 66 in Human Breast Cancer sample, ER-α 46 and ER-α 36 express.1 road: normal mammary tissue; 2 roads: infitrating ductal carcinoma; 3 roads: infitrating ductal carcinoma; 4 roads: aggressive duct carcinoma; 5 roads: infiltrating lobular carcinoma; 6 roads: infiltrating lobular carcinoma; 7 roads: non-infiltration duct carcinoma.
Fig. 2 is MDA-MB-231 immunofluorescent staining result, this cell is the estrogen receptor negative breast cancer cell line of disappearance ER-α 66 and ER-α 46, and use can be with the antibody of ER-α 36 specific bindings to its dye (being designated as " ER-α 36 ": positive staining is shown in green) in figure.With 4,6-diamidino-2-phenylindone to nucleus dye (being designated as " DAPI " in figure: positive staining is shown as blueness).The dyeing signal merging is denoted as " merging ".After antibody is combined with immunogenic peptide preculture, we find that dyeing is negative.
embodiment 1
According to above embodiment 1, the compound of formula (I) can be prepared by several steps.Formula 1 compound is reacted in inert solvent to condensation preparation formula 3 compounds with formula 2 compounds.The solvent that is applicable to this reaction comprises ether, as DME (1,2-glycol dimethyl ether) and 1,2-diethoxyethane; THF, DMF; N,N-dimethylacetamide and METHYLPYRROLIDONE.Reaction solvent is preferably 1,2-glycol dimethyl ether and 1,2-diethoxyethane.When reaction, can add as the additive of the stoichiometries such as triethylamine and N-ethyl-N-sec.-propyl third-2-amine or catalytic amount.Temperature when reaction is carried out is conventionally between approximately 0 DEG C to approximately 140 DEG C, and reaction keeps approximately 1 to 20 hours while being preferably in solvent refluxing temperature.
Can be by protecting the 7-hydroxyl of compound 3 to carry out preparation formula 4 compounds with ether in inert reaction solvent.The solvent that is applicable to this reaction comprises that ether is as DME (1,2-glycol dimethyl ether) and 1,2-diethoxyethane; THF, DMF; N, N-acetic acid dimethylamide and METHYLPYRROLIDONE.The solvent using in reaction is preferably DMF.When reaction, can add as the additive of the stoichiometries such as triethylamine and N-ethyl-N-sec.-propyl third-2-amine or catalytic amount.Temperature of reaction is conventionally between approximately 0 DEG C to approximately 80 DEG C, and the reaction times is about 1 to 20 hours.
Formula 4 compounds and bromide can be put into inert solvent and react preparation formula 5 compounds.The solvent that is applicable to this reaction comprises that ether is as DME (1,2-glycol dimethyl ether) and 1,2-diethoxyethane; THF; DMF; N, N-acetic acid dimethylamide and METHYLPYRROLIDONE; Methylene dichloride; Trichloromethane.Reaction solvent is preferably methylene dichloride.When reaction, can add as the additive of the stoichiometries such as triethylamine, N-ethyl-N-sec.-propyl third-2-amine and TBAH or catalytic amount.The alkali using in reaction is preferably TBAH.Temperature of reaction is conventionally between approximately 0 DEG C to approximately 80 DEG C, and the reaction times is about 1 to 20 hours.
Can be by heating-type 5 compound preparation formula 6 compounds in inert solvent.The solvent that is applicable to this reaction comprises that ether is as DMF; N, N-acetic acid dimethylamide and METHYLPYRROLIDONE; N, N-Diethyl Aniline; DMA.The solvent using in reaction is preferably N, N-Diethyl Aniline.Temperature of reaction is conventionally between approximately 50 DEG C to approximately 300 DEG C, and the reaction times is about 1 to 20 hours.Temperature of reaction is preferably between approximately 200 DEG C to approximately 300 DEG C, and the reaction times is about 1 to 20 hours.
Can be by slough protecting group preparation formula 7 compounds of formula 6 compounds in inert solvent.The solvent that is applicable to this reaction comprises that ether is as DME (1,2-glycol dimethyl ether) and 1,2-diethoxyethane; Dioxane; Alcohols is as methyl alcohol, ethanol and Virahol; THF; DMF; N, N-acetic acid dimethylamide and METHYLPYRROLIDONE; Methylene dichloride; Trichloromethane.Reaction solvent is preferably Virahol.Temperature of reaction is conventionally between approximately 0 DEG C to approximately 150 DEG C, and the reaction times is about 10 minutes to 20 hours.Temperature of reaction is preferably between approximately 10 DEG C to approximately 80 DEG C, and the reaction times is about 30 minutes to 4 hours.
Formula 7 compounds can be reacted to preparation formula 8 compounds under acidic conditions in inert solvent.The solvent that is applicable to this reaction comprises ether, as DME and 1,2-diethoxyethane; Dioxane; Alcohols is as methyl alcohol, ethanol and Virahol; Acetone; THF; DMF; N, N-acetic acid dimethylamide and METHYLPYRROLIDONE; Or the mixture of above-mentioned solvent and water.The solvent using in reaction is preferably acetone-water (1:1v/v).Temperature of reaction is conventionally between approximately 0 DEG C to approximately 150 DEG C, and the reaction times is about 10 minutes to 20 hours.Temperature of reaction is preferably between approximately 50 DEG C to approximately 100 DEG C, and the reaction times is about 2 minutes to 8 hours.
Formula 8 compounds can be reacted to preparation formula 9 compounds with 2-chloromethyl cyanide.This reaction can not used solvent, also can use solvent, applicable solvent to comprise that ether is as DME and 1,2-diethoxyethane; Dioxane; THF; DMF; N, N-acetic acid dimethylamide and METHYLPYRROLIDONE.Temperature of reaction is conventionally between approximately-50 DEG C to approximately 50 DEG C, and the reaction times is about 1 to 20 hours.Temperature of reaction is preferably between approximately-20 DEG C to approximately 50 DEG C, and the reaction times is about 2 to 8 hours.
Formula 9 compounds can be reacted under acidic conditions in inert solvent to preparation formula 10 compounds with thiocarbamide.The solvent that is applicable to this reaction comprises that ether is as DME and 1,2-diethoxyethane; Dioxane; Alcohols is as methyl alcohol, ethanol and Virahol; Acetone; THF; DMF; N, N-acetic acid dimethylamide and METHYLPYRROLIDONE; Temperature of reaction is conventionally between approximately 0 DEG C to approximately 200 DEG C, and the reaction times is about 1 to 100 hours.Temperature of reaction is preferably between approximately 60 DEG C to approximately 150 DEG C, and the reaction times is about 30 to 50 hours.
embodiment 2
R in embodiment 2
5, R
6, R
14, R
15with
definition as previously mentioned, can through type 11 and formula 12 compound preparation formula 13 compounds.Conventionally formula 11 compounds and formula 12 compound can be put into and react as acidic aqueous solutions such as citric acid solutions, heating makes temperature reach about envrionment temperature extremely between approximately 100 DEG C, preferably at solvent refluxing temperature, keep approximately 1 to approximately 10 hours, preferably at 4 to 6 hours.
Can through type 13 and formula 14 compound preparation formula 15 compounds.Formula 13 compounds and formula 14 compounds can reacted to preparation formula 15 compounds in inert solvent under the acidic conditionss such as tosic acid as contained.The solvent that is applicable to this reaction comprises ether, as toluene, DME, 1,2-diethoxyethane; Dioxane; THF; DMF; N, N-acetic acid dimethylamide and METHYLPYRROLIDONE, be preferably toluene; Temperature of reaction is conventionally between approximately 60 DEG C to approximately 200 DEG C, and the reaction times is about 1 to 100 hours.Temperature of reaction is preferably between approximately 90 DEG C to approximately 120 DEG C, and the reaction times is about 10 to 30 hours.
Can be by heating-type 15 compound preparation formula 16 compounds in inert solvent.The solvent that is applicable to this reaction comprises ether, as phenyl ether, toluene, DME, 1,2-diethoxyethane; Dioxane; THF; DMF; N, N-acetic acid dimethylamide and METHYLPYRROLIDONE; Be preferably phenyl ether.Temperature of reaction is conventionally between approximately 60 DEG C to approximately 200 DEG C, and the reaction times is about 1 to 20 hours.Temperature of reaction is preferably between approximately 90 DEG C to approximately 150 DEG C, and the reaction times is about 5 to 15 hours.
Can carry out preparation formula 17 and 18 compounds by the similar approach of preparation formula 8,9 and 10 compounds described in preparation scheme 1.
embodiment 3
In embodiment 3 P and
definition as previously mentioned, can through type 19 and formula 20 compound preparation formula 21 compounds.Conventionally mixing of formula 19 compounds and formula 20 compounds can be placed in microwave reactor and be heated between approximately 150 DEG C to 200 DEG C, the reaction times is 1 to 30 minute.
Can be by protect the compound of the 7-hydroxyl preparation formula 22 of compound 21 with ether in inert reaction solvent.The solvent that is applicable to this reaction comprises ether, as DME and 1,2-diethoxyethane; THF, DMF; N, N-acetic acid dimethylamide and METHYLPYRROLIDONE.The solvent using in reaction is preferably DMF.When reaction, can add as the additive of the stoichiometries such as triethylamine and N-ethyl-N-sec.-propyl third-2-amine or catalytic amount.Temperature of reaction is conventionally between approximately 0 DEG C to approximately 80 DEG C, and the reaction times is about 1 to 20 hours.
Formula 22 compounds and bromide can be put into inert solvent and react preparation formula 23 compounds.The solvent that is applicable to this reaction comprises ether, as DME and, 1,2-diethoxyethane; THF; DMF; N, N-acetic acid dimethylamide and METHYLPYRROLIDONE; Methylene dichloride; The mixture of trichloromethane and toluene or above-mentioned solvent.Reaction solvent is preferably methylene dichloride.When reaction, can add as the additive of the stoichiometries such as triethylamine, N-ethyl-N-sec.-propyl third-2-amine and TBAH or catalytic amount.The alkali using in reaction is preferably TBAH.Temperature of reaction is conventionally between approximately 0 DEG C to approximately 80 DEG C, and the reaction times is about 1 to 20 hours.
Can be by heating-type 23 compound preparation formula 24 compounds in reaction-inert solvent.The solvent that is applicable to this reaction comprises ether, as DMF; N, N-acetic acid dimethylamide and METHYLPYRROLIDONE; N, N-Diethyl Aniline; DMA.The solvent using in reaction is preferably N, N-Diethyl Aniline.Temperature of reaction is conventionally between approximately 50 DEG C to approximately 300 DEG C, and the reaction times is about 1 to 20 hours.Temperature of reaction is preferably between approximately 200 DEG C to approximately 300 DEG C, and the reaction times is about 1 to 20 hours.
Can be by slough protecting group preparation formula 25 compounds of formula 24 compounds in reaction-inert solvent.The solvent that is applicable to this reaction comprises that ether is as DME and 1,2-diethoxyethane; Dioxane; Alcohols is as methyl alcohol, ethanol and Virahol; THF; DMF; N, N-acetic acid dimethylamide and METHYLPYRROLIDONE; Methylene dichloride; Trichloromethane.Temperature of reaction is conventionally between approximately 0 DEG C to approximately 150 DEG C, and the reaction times is about 10 minutes to 20 hours.Temperature of reaction is preferably between approximately 10 DEG C to approximately 80 DEG C, and the reaction times is about 30 minutes to 4 hours.
Can carry out preparation formula 26 and 27 compounds by the similar approach of preparation formula 8,9 and 10 compounds described in preparation scheme 1.
embodiment 4
R in embodiment 4
14, R
15with
definition as previously mentioned, can through type 28 preparation formula 29 compounds.Conventionally can be by formula 28 compounds in reaction-inert solvent and isoprenyl bromide Hybrid Heating between approximately 10 DEG C to 100 DEG C, the reaction times is 2 to 3 hours.The solvent that is applicable to this reaction comprises ether, as DME and 1,2-diethoxyethane; Dioxane.Temperature of reaction is preferably between approximately 10 DEG C to approximately 80 DEG C, and the reaction times is about 5 to 20 hours.
Can through type 29 and formula 30 compound preparation formula 31 compounds.Conventionally formula 29 compounds and formula 30 compound can be put into microwave reactor and be heated between approximately 150 DEG C to 300 DEG C, the reaction times is 1 to 60 minute.
The similar approach of preparation formula 8,9 and 10 compounds of describing in useful embodiment 1 is carried out the compound of preparation formula 32 and 33.
Embodiment and preparation method
By following nonrestrictive embodiment, the present invention is set forth, unless otherwise described, otherwise: room temp or envrionment temperature refer within the scope of 18-25 DEG C; Solvent evaporates with rotary evaporator under reduced pressure; Reaction process is monitored by thin layer chromatography (TLC).Reaction times is only for setting forth explanation; Shown in fusing point (m.p.) not through overcorrection (polymorphism may produce different fusing points); Confirm to separate structure and the purity of the compound obtaining by least following a kind of technology: TLC, mass spectrum, nucleus magnetic resonance (NMR), high performance liquid chromatography (HPLC).Described productive rate is only for setting forth explanation.
Preparation 5,7-dihydroxyl-3-methoxyl group-2-(3,4-Dimethoxyphenyl)-4H-benzopyran-4-one (compound 1).
By 3,4-dimethoxybenzoic acid acid anhydride (26.0g, 75mmol), 1-(2,4,6-trihydroxy-phenyl)-2-methoxyl group ethyl ketone (5.0g, 25mmol), NEt
3(10mL), 4A MS (10.0g) and DME (40mL) mix backflow 10 hours.After it is cooled to room temperature, the methyl alcohol that adds 150mL to contain 9.2g potassium hydroxide, then the mixture obtaining is refluxed 2 hours, in reaction mixture, add water, with hydrochloric acid (6N), the mixture obtaining is neutralized to pH value and is about 8.With 100mL EtOAc extractive reaction mixed solution 3 times.Collect organic solvent extraction thing and use dried over sodium sulfate.Remove after solvent, with silica gel chromatography, resistates is carried out to purifying and obtain target compound (6.5g, 0.19mol, productive rate 74%).
1H NMR(400MHz,DMSO-d6):δ＝12.64(s,1H),10.86(s,1H),7.69(m,2H),7.62(d,1H,J＝1.6Hz),7.15(d,1H,J＝12.8Hz),6.49(d,1H,J＝2.0Hz),6.22(d,1H,J＝2.0Hz),3.86(s,6H),3.81(s,3H)。
Preparation 5-hydroxy-3-methoxy-7-(methoxymethoxy)-2-(3,4-Dimethoxyphenyl)-4H-benzopyran-4-one (compound 2)
Containing 5,7-dihydroxyl-3-methoxyl group-2-(3,4-Dimethoxyphenyl)-4H-benzopyran-4-one (17.0g, 50mmol) and in the solution of dry DMF (140mL) stir and add N, N-diisopropylethylamine (7.6g, 59mmol), then by chloromethyl methyl ether (4.8g, 60mmol) be added in mixture.Reaction mixture is stirred 4 hours under the condition of room temp.Dilute with water reaction mixture, is adjusted to 1 left and right (1N hydrochloric acid) by pH value.With EtOAc extractive reaction mixed solution.Collect EtOAc extract, water rinses, and makes it concentrated under reduced pressure.Obtain work in-process removing after solvent, then by silica gel chromatography, resistates is carried out to purifying and obtain target compound (7.0g, 36%).
1H NMR(400MHz,CDCl
3)δ＝12.60(brs,1H),7.75(dd,1H,J
1＝2.0Hz,J
2＝8.4Hz),7.70(d,1H,J＝2.0Hz),7.00(d,1H,J＝8.8Hz),6.63(d,1H,J＝2.4Hz),6.47(d,1H,J＝2.0Hz),5.25(s,2H),3.98(s,3H),3.97(s,3H),3.87(s,3H),3.51(s,3H)；LCMS(ESI)m/z389[M+H]
+。
Preparation 5-(3-methyl but-2-ene base oxygen base)-3-methoxyl group-7-(methoxymethoxy)-2-(3,4-Dimethoxyphenyl)-4H-benzopyran-4-one (compound 3).
Containing 5-hydroxy-3-methoxy-7-(methoxymethoxy)-2-(3,4-Dimethoxyphenyl)-4H-benzopyran-4-one (5.0g, in methylene dichloride (100mL) solution 13mmol), stir and add TBAH (100g, 33mmol, concentration 10% in water), again isoprenyl bromide (8.0g, 53mmol) is added in said mixture, reaction mixture is stirred 3 hours at ambient temperature.Dilute with water reaction mixture.With EtOAc extractive reaction mixed solution, collect EtOAc extract, water rinses, and makes it concentrated under reduced pressure.Obtain work in-process removing after solvent, then by silica gel chromatography, resistates is carried out to purifying and obtain target compound (5.5g, 93%).
1H NMR(400MHz,CDCl
3)δ＝7.71(m,2H),6.97(d,1H,J＝9.2Hz),6.71(d,1H,J＝2.0Hz),6.44(d,1H,J＝2.4Hz),5.60(t,1H,J＝6.4Hz),5.26(s,1H),4.70(d,1H,J＝6.0Hz),3.97(s,3H),3.96(s,3H),3.87(s,3H),3.52(s,3H),1.77(d,6H,J＝10.8Hz)；LCMS(ESI)m/z457[M+H]
+。
Preparation 5-hydroxy-3-methoxy-7-(methoxymethoxy)-2-(3,4-Dimethoxyphenyl)-8-(3-methyl fourth 2-thiazolinyl)-4H-benzopyran-4-one (compound 4).
By 5-(3-methyl but-2-ene base oxygen base)-3-methoxyl group-7-(methoxymethoxy)-2-(3,4-Dimethoxyphenyl)-4H-benzopyran-4-one (2.3g, 5.0mmol) and N, N-diethyl-aniline (100mL) is Hybrid Heating under 217 DEG C of conditions, stirs 3 hours.After it is cooled to room temperature, dilute with water reaction mixture by its acidifying (pH1,1N hydrochloric acid).With EtOAc extraction, collect organic extract water and rinse.Under reduced pressure, by solvent evaporation, then by silica gel chromatography, resistates is carried out to purifying and obtain target compound (1.75g, 76%).
1H NMR(400MHz,DMSO-d
6)δ＝12.61(s,1H),7.71(dd,1H,J
1＝2.0Hz,J
2＝8.6Hz),7.66(d,1H,J＝2.0Hz),7.19(d,1H,J＝8.6Hz),6.58(s,1H),5.36(s,2H),5.22(t,1H,J＝7.0Hz),3.87(s,3H),3.84(s,3H),3.83(s,3H),3.49(d,2H,J＝6.8Hz),3.40(s,3H),1.77(d,6H,J＝5.6Hz)；LCMS(ESI)m/z457[M+H]
+。
Preparation 5,7-dihydroxyl-3-methoxyl group-2-(3,4-Dimethoxyphenyl)-8-(3-methyl but-2-ene base)-4H-benzopyran-4-one (compound 5).
By 5-hydroxy-3-methoxy-7-(methoxymethoxy)-2-(3,4-Dimethoxyphenyl)-8-(3-methyl but-2-ene base)-4H-benzopyran-4-one (0.91g, 2.0mmol), 4N hydrochloric acid (10mL) and Virahol (30mL) Hybrid Heating under 65 DEG C of conditions, continue 1 hour.After it is cooled to room temperature, with EtOAc extractive reaction mixed solution.Water rinses EtOAc extract, is dried with sodium sulphite, and under reduced pressure, solvent is evaporated.By silica gel chromatography, the resistates obtaining is carried out to purifying again and obtain target compound (0.72g, 87%).
1h NMR (400MHz, acetone-d
6) δ=12.69 (s, 1H), 9.59 (s, 1H), 7.78 (dd, 1H, J
1=2.0Hz, J
2=8.5Hz), 7.74 (d, 1H, J=2.0Hz), 7.13 (d, 1H, J=8.5Hz), 6.33 (s, 1H), 5.30 (t, 1H, J=6.8Hz), 3.91 (s, 3H), 3.90 (s, 6H), 3.52 (d, 1H, J=6.8Hz), 1.60 (d, 6H, J=48Hz); LCMS (ESI) m/z413[M+H]
+.
Preparation 5,7-dihydroxyl-8-(3-hydroxy-3-methyl butyl)-3-methoxyl group-2-(3,4-Dimethoxyphenyl)-4H-benzopyran-4-one (compound 6).
By 5,7-dihydroxyl-3-methoxyl group-2-(3,4-Dimethoxyphenyl)-8-(3-methyl fourth-2 thiazolinyl)-4H-benzopyran-4-one (91mg, 0.2mmol), 5% sulfuric acid (5mL) and acetone (20mL) Hybrid Heating under 65 DEG C of conditions, continue 5 hours.After it is cooled to room temperature, with EtOAc extractive reaction mixed solution.Collect EtOAc extract water and rinse, be dried with sodium sulphite, and under reduced pressure, solvent evaporated.By silica gel chromatography, the resistates obtaining is carried out to purifying again and obtains target compound (10mg, 12%).
1h NMR (400MHz, DMSO-d
6) δ=12.57 (s, 1H), 10.71 (s, 1H), 7.74 (d, 1H, J=8.4Hz), 7.67 (s, 1H), 7.11 (d, 1H, J=8.4Hz), 6.29 (s, 1H), 4.27 (brs, 1H), 3.84 (s, 6H), 3.80 (s, 3H), 2.76 (m, 2H), 1.54 (m, 2H), 1.15 (s, 6H); LCMS (ESI) m/z431[M+H]
+.
The preparation chloro-N-of 2-(4-(3,5,7-trihydroxy--2-(4-p-methoxy-phenyl)-4-oxygen base-4H-chromene-8-yl)-2-methyl fourth-2-yl) ethanamide (compound 7).
Containing 3,5,7-trihydroxy--8-(3-hydroxy-3-methyl butyl)-2-(4-methoxyphenyl)-4H-benzopyran-4-one (0.94g, 2-chloromethyl cyanide (49mL 2.4mmol), 780mmol) in solution, dropwise add Glacial acetic acid (1.7mL, 29mmol).By 15 DEG C of this resulting solution Leng Que Zhi –, more dropwise add concentrated thiosulfonic acid (1.7mL, 31mmol).Under 20 DEG C of conditions, reaction mixture is stirred 4 hours.Again this reaction mixture is poured in ice, obtained mixture with saturated sodium bicarbonate aqueous solution alkalization, then extract with EtOAc.Use dried over sodium sulfate organic horizon, under reduced pressure, be condensed into work in-process, be purified by silicon column chromatography (c-hexane/EtOAc, 3:1), obtain target compound (650mg, 58%), a kind of yellow solid.
1H NMR(500MHz,DMSO-d
6)δ1.35(6H,s),1.86-1.89(2H,m),2.68-2.71(2H,m),3.85(3H,s),4.02(2H,s),6.29(1H,s),7.12-7.15(2H,m),7.73(1H,s),8.17-8.19(2H,m),9.47(1H,s),10.68(1H,s),12.38(1H,s)；
13C NMR(125MHz,DMSO-d
6)δ17.12,26.22(2),42.57,43.44,53.22,55.36,97.79,102.99,106.22,114.08(2C),123.56,129.31(2),135.85,146.13,153.43,158.24,160.46,161.36,165.02,176.27；ESIMS462[M+H]
+。
Preparation 8-(3-amino-3-methyl butyl)-3,5,7-trihydroxy--2-(4-p-methoxy-phenyl)-4H-benzopyran-4-one (compound 8).
By chloro-2-N-(4-(3,5,7-trihydroxy--2-(4-methoxyphenyl)-4-carbonyl-4H-chromene-8-yl)-2-methyl fourth-2-yl) ethanamide (650mg, 1.41mmol), thiocarbamide (130mg, 1.69mmol), Glacial acetic acid (1.4mL) and EtOH (100mL) mixing solutions reflux 50 hours.Again compound of reaction is cooled to room temperature and by its filtration.Filtrate is concentrated, alkalize with saturated sodium bicarbonate aqueous solution, then extract with EtOAc.The organic solution of collecting with strong brine washing, uses dried over sodium sulfate organic horizon, by its simmer down to work in-process, by silica gel chromatography (methylene dichloride/ethanol, 4:1) carry out purifying and obtain target compound (210mg, 37%), a kind of yellow solid.
1H NMR(500MHz,DMSO-d
6)δ1.37(6H,s),1.73-1.77(2H,m),2.75-2.78(2H,m),3.85(3H,s),6.39(1H,s),7.12-7.13(2H,m),8.14-8.16(2H,m),9.51(1H,s),10.97(1H,s),12.38(1H,s)；
13C NMR(125MHz,DMSO-d
6)δ16.76,24.43(2),53.50,55.41,55.99,97.97,102.92,105.08,114.05(2),123.56,129.27(2),135.99,146.08,153.43,158.48,160.46,161.77,176.26；ESIMS386[M+H]
+。
Preparation 8-(3-amino-3-methyl butyl)-3,5, the hydrochloride (compound 9) of 7-trihydroxy--2-(4-p-methoxy-phenyl)-4H-benzopyran-4-one.
Containing 8-(3-amino-3-methyl butyl)-3,5,7-trihydroxy--2-(4-methoxyphenyl)-4H-benzopyran-4-one (210mg, in dehydrated alcohol (20mL) suspension 0.55mmol), dropwise add dehydrated alcohol (5mL) solution that contains concentrating hydrochloric acid (0.8mL, 9.6mmol).Reaction mixture is stirred 30 minutes to the concentrated target compound, a kind of yellow solid of obtaining under reduced pressure.
1h NMR (500MHz, DMSO-d
6) δ 1.37 (6H, s), 1.72-1.75 (2H, m), 2.76-2.79 (2H, m), 3.86 (3H, s), 6.35 (1H, s), 7.12-7.13 (2H, m), 7.90 (3H, brs), 8.14-8.16 (2H, m), 9.54 (1H, s), 10.89 (1H, s), 12.38 (1H, s);
13c NMR (125MHz, DMSO-d
6) δ 16.71,24.41 (2), 53.61,55.42,97.81,103.06,105.01,114.06 (2), 123.51,129.27 (2), 135.95,146.16,153.44,158.54,160.51,161.37,176.26; ESIMS386[M-hydrochloric acid+H]
+.
Preparation 2-(4-chloro-phenyl-)-5,7-dihydroxyl-3-methoxyl group-4H-benzopyran-4-one (compound 10)
By 4-chlorobenzene acid anhydrides (31.3g, 106mmol), 1-(2,4,6-trihydroxy-phenyl)-2-methoxyl group ethyl ketone (7.0g, 35mmol), NEt
3(10mL), the mixture of 4A MS (10.0g) and DME (70mL) refluxes 10 hours.Be cooled to after room temperature, the methyl alcohol that contains potassium hydroxide (9.2g) (150mL) is added in this mixture, this mixture is refluxed 2 hours.Be cooled to after room temperature, then add water, with hydrochloric acid (6N), mixture being neutralized to pH value is 8.Extract mixture 3 times with 100mL EtOAc again, it is dried and evaporates.Obtain target compound (4.3g, 38%) .LCMS (ESI) m/z319.7 (M+H) by silica gel chromatography purifying work in-process
+.
Preparation 2-(4-chloro-phenyl-)-5-hydroxy-3-methoxy-7-(methoxymethoxy)-4H-benzopyran-4-one (compound 11)
Containing 2-(4-chloro-phenyl-)-5,7-dihydroxyl-3-methoxyl group-4H-benzopyran-4-one (4.3g, 13.3mmol,) the solution of dry DMF (40mL) in stir and add N, N-diisopropylethylamine (2.1g, 16mmol), then add chloromethyl methyl ether (1.3g, 15.8mmol).Reaction mixture is stirred 4 hours under room temp.Dilute with water reaction mixture, makes pH value be adjusted to 1 (1N hydrochloric acid), and extracts with EtOAc.Water rinses extract, under reduced pressure, is concentrated.Obtain target compound (3.80g, 79%) by silica gel chromatography purifying work in-process.LCMS(ESI)m/z363.8[M+H]
+。
Preparation 5-(3-methyl but-2-ene base oxygen base)-2-(4-chloro-phenyl-)-3-methoxyl group-7-(methoxymethoxy)-4H-benzopyran-4-one (compound 12)
Containing 2-(4-chloro-phenyl-)-5-hydroxy-3-methoxy-7-(methoxymethoxy)-4H-benzopyran-4-one (3.80g, in methylene dichloride (100mL) solution 10.5mmol), stir and add TBAH (80.0g, 26.0mmol, concentration 10% in water), add again isoprenyl bromide (6.3g, 42mmol).Reaction mixture is at room temperature stirred 3 hours.Dilute with water mixture, and extract with EtOAc.Collect extract dry.Obtain target compound (3.83g, 85%) by silica gel chromatography purifying work in-process.LCMS(ESI)m/z431.4[M+H]
+。
Preparation 2-(4-chloro-phenyl-)-5-hydroxy-3-methoxy-7-(methoxymethoxy)-8-(3-methyl but-2-ene base)-4H-benzopyran-4-one (compound 13)
By 5-(3-methyl but-2-ene base oxygen base)-2-(4-chloro-phenyl-)-3-methoxyl group-7-(methoxymethoxy)-4H-benzopyran-4-one (1.60g, 3.7mmol) and N, N-diethyl-aniline (70mL) is slowly heated to 217 DEG C, stirs 3 hours.Be cooled to after room temp, by reaction mixture dilute with water acidifying (pH1,1N hydrochloric acid), then extract with EtOAc.Collect EtOAc extract, water rinses, and evaporation under reduced pressure, by silica gel chromatography, residue purified is obtained to target compound target compound (0.80g, 50%).
1h NMR (400MHz, acetone-d
6) δ=12.61 (s, 1H), 8.15 (d, 2H, J=8.8Hz), 7.65 (d, 2H, J=8.8Hz), 6.61 (s, 1H), 5.40 (s, 2H), 5.22 (t, 1H, J=6.8Hz), 3.93 (s, 3H), 3.55 (d, 2H, J=6.8Hz), 3.49 (s, 3H), 1.79 (s, 3H), 1.66 (s, 3H); LCMS (ESI) m/z431.8[M+H]
+.
Preparation 2-(4-chloro-phenyl-)-5,7-dihydroxyl-3-methoxyl group-8-(3-methyl but-2-ene base)-4H-benzopyran-4-one
(compound 14)
By 2-(4-chloro-phenyl-)-5-hydroxy-3-methoxy-7-(methoxymethoxy)-8-(3-methyl but-2-ene base)-4H-benzopyran-4-one (0.80g, 1.85mmol), 4N hydrochloric acid (5mL) and Virahol (30mL) Hybrid Heating 2 hours under 50 DEG C of conditions.Be cooled to after room temperature, with EtOAc extractive reaction mixed solution.Water rinses EtOAc extract, is dried with sodium sulfate, and evaporation under reduced pressure.Obtain target compound target compound (0.58g, 81%) by silica gel chromatography purifying resistates.
1h NMR (400MHz, acetone-d
6) δ=12.59 (s, 1H), 9.69 (s, 1H), 8.15 (d, 2H, J=8.8Hz), 7.65 (d, 2H, J=8.8Hz), 6.38 (s, 1H), 5.25 (t, 1H, J=6.8Hz), 3.93 (s, 3H), 3.52 (d, 2H, J=6.8Hz), 1.77 (s, 3H), 1.66 (s, 3H); LCMS (ESI) m/z384.9[M-H]
-.
Preparation 3-amino-2-(3-methyl but-2-ene base) phenol (compound 15)
By Metha Amino Phenon (5.45g, 50mmol), 2-methyl fourth-3-alkene-2-alcohol (4.30g, 50mmol) and aqueous citric acid solution (5%, 50mL) Hybrid Heating 6 hours under 100 DEG C of conditions, be cooled to after room temperature, rinse mixture with saturated sodium bicarbonate solution, be dried with sodium sulfate, concentrated in a vacuum.Again by silica gel chromatography purifying work in-process, and make its crystallization by sherwood oil and ethyl acetate (v:v=3:1), obtain productive rate and be 10% target compound (0.87g).
1H-NMR(400MHz,CDCl
3):δ＝6.89(t,1H,J＝8.0Hz),6.31(d,1H,J＝8.0Hz),6.25(d,1H,J＝8.0Hz),5.16(t,1H,J＝6.8Hz),4.81(brs,1H),3.68(brs,2H),3.31(d,1H,J＝6.8Hz),1.78(d,6H,J＝32Hz)；LCMS(ESI)m/z178.1(M+H)
+。
Preparation (Z)-ethyl 3-(3-hydroxyl-2-(3-methyl but-2-ene base) anilino)-3-(4-p-methoxy-phenyl) acrylate (compound 16)
By 3-amino-2-(3-methyl but-2-ene base) phenol (0.87g, 5.0mmol), ethyl 3-(4-methoxyphenyl)-3-carbonyl propionic acid ester (0.67g, 3.0mmol) and tosic acid (0.05g, 0.3mmol) in toluene (10mL) Hybrid Heating reflux 24 hours.Be cooled to after room temperature, methylene dichloride (30mL) is being added in reaction mixture.Rinse organic horizon 3 times with 10mL water, be dried with sodium sulfate, make it concentrated.By silica gel chromatography purifying work in-process, using sherwood oil and ethyl acetate (v:v=20:1) to obtain productive rate is 40% target compound (0.42g); LCMS (ESI) m/z382.2 (M+H)
+.
Preparation 7-hydroxyl-2-(4-methoxyphenyl)-8-(3-methyl but-2-ene) quinoline-4 (1H)-one (compound 17)
Ethyl 3-(3-hydroxyl-2-(3-methyl but-2-ene base) anilino)-3-phenyl acrylate (0.42g, 1.20mmol) is dissolved in phenyl ether in (20mL) to reflux 5 hours.Remove after solvent, obtain target compound (0.20g, 54%) by silica gel chromatography purifying work in-process.
1H-NMR(CDCl
3):δ＝8.04(d,1H,J＝8.8Hz),7.55(d,2H,J＝8.4Hz),7.04(d,2H,J＝8.4Hz),6.96(d,1H,J＝8.8Hz),6.49(s,1H),5.30(t,1H,J＝6.4Hz),3.90(s,3H),3.71(d,2H,J＝6.4Hz),3.70(brs,1H),1.82(d,6H,J＝34Hz)；LCMS(ESI)m/z336.2(M+H)
+。
Preparation 2-(4-chloro-phenyl-)-5,7-dihydroxyl-4H-benzopyran-4-one (compound 18)
By methyl 3-(4-chloro-phenyl-)-3-carbonyl propionic acid ester (10.6g, 50mmol) and 1,3,5-trihydroxybenzene (8.1g, 50mmol) hybrid reaction 3 times in microwave reactor (170 DEG C, move 1 minute, stop 3 minutes).This intermediate is diluted with EtOAc, filter and obtain target compound (3.5g, 24.2%).LCMS(ESI):m/z289[M+H]
+。
Preparation 2-(4-chloro-phenyl-)-5-hydroxyl-7-(methoxymethoxy)-4H-benzopyran-4-one (compound 19).
Containing 2-(4-chloro-phenyl-)-5,7-dihydroxyl-4H-benzopyran-4-one (8.8g, in the solution of dry DMF (80mL) 30.6mmol), stir and add N, N-diisopropylethylamine (4.7g, 36.7mmol), in mixture, add chloromethyl methyl ether (2.95g, 36.7mmol) again.Stirring reaction mixed solution 4 hours at ambient temperature.Again reaction mixture is poured in water (400ml), filtered and obtain the work in-process that directly use in step afterwards without purifying.
1hNMR (400M, acetone-d6) δ=12.78 (s, 1H), 8.14 (d, J=8.8,2H), 7.65 (d, J=8.8,2H), 6.89 (s, 1H), 6.82 (d, J=2.0Hz, 1H), 6.45 (d, J=2.0Hz, 1H), 5.36 (s, 1H), 3.50 (s, 3H); LCMS (ESI): m/z332[M+H]
+.
Preparation 5-(3-methyl but-2-ene base oxygen base)-2-(4-chloro-phenyl-)-7-(methoxymethoxy)-4H-benzopyran-4-one (compound 20)
Containing 2-(4-chloro-phenyl-)-5-hydroxyl-7-(methoxymethoxy)-4H-benzopyran-4-one (10.0g, in DCM (100mL) 30mmol) and the solution of toluene (100mL), stir and add TBAH (153g, 33mmol, 10% the aqueous solution), add again isoprenyl bromide (8.74g, 60mmol, 2eq), reaction mixture is stirred 3 hours under room temp condition.Water (100mL) diluting reaction mixed solution, extracts with EtOAc.After removing solvent, obtain work in-process, obtain target compound (8.0g, 67%) by silica gel chromatography purifying.
1hNMR (400M, acetone-d6) δ=8.05 (d, J=8.4,2H), 7.60 (d, J=8.4,2H), 6.87 (s, 1H), 6.63 (s, 1H), 6.60 (s, 1H), 5.53 (t, J=6.8,, 1H), 5.35 (s, 1H), 4.70, (d, J=6.8,2H) 3.50 (s, 3H), 1.79 (s, 3H), 1.78 (s, 3H); LCMS (ESI): m/z401[M+H]
+.
Preparation 2-(4-chloro-phenyl-)-5-hydroxyl-7-(methoxymethoxy)-8-(3-methyl but-2-ene base)-4H-benzopyran-4-one (compound 21)
By 5-(3-methyl but-2-ene base oxygen base)-2-(4-chloro-phenyl-)-7-(methoxymethoxy)-4H-benzopyran-4-one (4.5g, 11.2mmol) and N, N-diethyl-aniline (400mL) Hybrid Heating under 217 DEG C of conditions stirs 3 hours.Be cooled to after room temperature, reaction mixture poured in the hydrochloric acid soln of dilution.Carry out collecting precipitation thing by filtration, be placed in EtOAc and sherwood oil (v/v=1:1) and make its crystallization obtain target compound (2.0g, 44.6%).
1hNMR (400M, acetone-d6) δ=12.81 (s, 1H), 8.10 (d, J=8.8,2H), 7.66 (d, J=8.8,2H), 6.85 (s, 1H), 6.60 (s, 1H), 5.40 (s, 2H), 5.27 (t, J=6.8,1H), 3.59, (d, J=6.8,2H), 3.50 (s, 3H), 1.84 (s, 3H), 1.68 (s, 3H); LCMS (ESI): m/z401[M+H]
+.
Preparation 2-(4-chloro-phenyl-)-5,7-dihydroxyl-8-(3-methyl but-2-ene base)-4H-benzopyran-4-one (compound 22)
Under 20 DEG C of conditions, by 2-(4-chloro-phenyl-)-5-hydroxyl-7-(methoxymethoxy)-8-(3-methyl but-2-ene base)-4H-benzopyran-4-one (0.5g, 2.0mmol) be dissolved in the mixture of methylene dichloride (20mL) and acetic acid (20mL), then add 7 concentrating hydrochloric acids.The mixture obtaining is stirred 18 hours under 20 DEG C of conditions.With collecting solid after saturated sodium bicarbonate solution washing and filtering, obtain target compound, a kind of yellow powder (0.3g, 42%).
1HNMR(400M,DMSO-d6)δ＝12.71(s,1H),11.04(s,1H),8.05(d,J＝8.4,2H),7.66(d,J＝8.4,2H),6.96(s,1H),6.37(s,1H),5.19(t,J＝6.8,1H),3.44,(d,J＝6.8,2H),1.76(s,3H),1.63(s,3H)；LCMS(ESI):m/z357[M+H]
+。
Preparation 2-(3-chloro-4-methoxy phenyl)-5,7-dihydroxyl-4H-benzopyran-4-one (compound 23)
By ethyl 3-(the chloro-4-methoxyphenyl of 3-)-3-carbonyl propionic acid ester (12.2g, 50mmol) and 1,3,5-trihydroxybenzene (8.1g, 50mmol) hybrid reaction 3 times in microwave reactor (160 DEG C, move 1 minute, stop 3 minutes).With EtOAc diluting reaction mixed solution, filter and obtain target compound (3.2g, 20.2%).
1HNMR(400M,DMSO-d6)δ＝12.84(s,1H),10.89(brs,1H,8.15(d,J＝2.0Hz,1H),8.04(dd,J
1＝2.0Hz,J
2＝8.8Hz,1H),7.30(d,J＝8.8,2H),6.96(s,1H),6.53(d,J＝2.0Hz,1H),6.20(d,J＝2.0Hz,1H),3.95(s,3H)；LCMS(ESI):m/z319[M+H]
+。
Preparation 2-(3-chloro-4-methoxy phenyl)-5-hydroxyl-7-(methoxymethoxy)-4H-benzopyran-4-one (compound 24).
Containing 2-(the chloro-4-methoxyphenyl of 3-)-5,7-dihydroxyl-4H-benzopyran-4-one (6.8g, in dry DMF (80mL) solution 21.5mmol), stir and add N, N-diisopropylethylamine (3.3g, 25.8mmol), again chloromethyl methyl ether (2.10g, 26.0mmol) is added to reaction mixture.Reaction mixture is stirred 4 hours under room temp condition.Reaction mixture is poured in water (400mL) again, after filtration, obtained the work in-process that can be directly use in step afterwards without purifying.
1HNMR(400M,DMSO-d6)δ＝12.79(s,1H),8.15(d,J＝2.0Hz,1H),8.04(dd,J
1＝2.0Hz,J
2＝8.4Hz,1H),7.27(d,J＝8.4,1H),7.00(s,1H),6.86(d,J＝2.0Hz,1H),6.41(d,J＝2.0Hz,1H),5.31(s,2H),3.95(s,3H),3.41(s,3H)；LCMS(ESI):m/z363[M+H]
+。
Preparation 5-(3-methyl but-2-ene base oxygen base)-2-(3-chloro-4-methoxy phenyl)-7-(methoxymethoxy)-4H-benzopyran-4-one (compound 25).
Containing 2-(3-chloro-4-methoxy phenyl)-5-hydroxyl-7-(methoxymethoxy)-4H-benzopyran-4-one (7.8g, in DCM (100mL) 21.5mmol) and the solution of toluene (100mL), stir and add TBAH (200g, 43mmol, 10% aqueous solution), add again isoprenyl bromide (12.5g, 86mmol, 2eq) to said mixture.Reaction mixture is stirred 3 hours at ambient temperature.Water (100mL) diluting reaction mixed solution, extracts with EtOAc.Collect organic horizon, be dried and evaporate.Obtain target compound (4.5g, 48%) by silica gel chromatography purifying work in-process.
1HNMR(400M,CDCl
3)δ＝7.91(d,J＝2.0Hz,1H),7.74(dd,J
1＝2.4Hz,J
2＝8.8Hz,1H),7.03(d,J＝8.8Hz,1H),6.77(d,J＝2.0Hz,1H),6.57(s,1H),6.47(d,J＝2.4Hz,1H),5.58(t,J＝6.4Hz,1H),5.27(s,2H),4.67(d,J＝6.4Hz,1H),3.98(s,3H),3.54(s,3H)；LCMS(ESI):m/z431[M+H]
+。
Preparation 2-(3-chloro-4-methoxy phenyl)-5-hydroxyl-7-(methoxymethoxy)-8-(3-methyl but-2-ene base)-4H-benzopyran-4-one (compound 26).
By 5-(3-methyl but-2-ene base oxygen base)-2-(the chloro-4-methoxyphenyl of 3-)-7-(methoxymethoxy)-4H-benzopyran-4-one (4.5g, 10.4mmol) and N, N-diethyl-aniline (400mL) heats under 217 DEG C of conditions, stirs 3 hours.Be cooled to after room temp, reaction mixture poured into the hydrochloric acid soln of dilution, throw out is filtered and used EtOAc and sherwood oil (v/v=1:1) make its crystallization obtain target compound (1.6g, 35.6%).
1hNMR (400M, acetone-d6) δ=12.87 (s, 1H), 8.09 (s, 1H), 8.04 (d, J=8.8,1H), 7.35 (d, J=8.8,1H), 6.78 (s, 1H), 6.58 (s, 1H), 5.39 (s, 1H), 5.26 (t, J=6.8,1H), 4.04 (s, 3H), 3.59 (d, J=6.4Hz, 2H), 3.49 (s, 3H), 1.87 (s, 3H), 1.69 (s, 3H); LCMS (ESI): m/z431[M+H]
+.
Preparation 2-(3-chloro-4-methoxy phenyl)-5,7-dihydroxyl-8-(3-methyl but-2-ene base)-4H-benzopyran-4-one (compound 27)
Under 20 DEG C of conditions by 2-(3-chloro-4-methoxy phenyl)-5-hydroxyl-7-(methoxymethoxy)-8-(3-methyl but-2-ene base)-4H-benzopyran-4-one (0.5g, 2.0mmol) be dissolved in the mixture of methylene dichloride (20mL) and acetic acid (20mL), then concentrating hydrochloric acid (0.15mL) is added in said mixture.The mixture obtaining is stirred 18 hours under 20 DEG C of conditions.The solid of collecting after filtering rinses and obtains target compound, a kind of yellow powder (0.32g, 41.5%) with saturated sodium bicarbonate solution.
1hNMR (400M, acetone-d6) δ=12.77 (s, 1H), 10.86 (s, 1H), 8.06 (s, 1H), 8.01 (d, J=8.8,1H), 7.33 (d, J=8.8,1H), 6.95 (s, 1H), 6.31 (s, 1H), 5.16 (t, J=6.4,1H), 3.95 (s, 3H), 3.43 (d, J=6.4Hz, 2H), 1.78 (s, 3H), 1.64 (s, 3H); LCMS (ESI): m/z387[M+H]
+.
Preparation 2-(3-methyl but-2-ene base) benzene-1,3-glycol (compound 28)
Sodium Metal 99.5 (1.04g, 45.22mmol) is added in batches in the ethereal solution (50mL) of Resorcinol (1.26g, 11.24mmol).Mixture was stirred after 1.5 hours, dropwise add isoprenyl bromide (1.70g, 11.24mmol), reaction mixture is refluxed 10 hours.Remove after unreacted sodium, make its acidifying with the hydrochloric acid (4mL) of 0.1M, and use extracted with diethyl ether.Use normal saline washing organic extract, by dried over sodium sulfate, concentrate and obtain work in-process in a vacuum, obtain target compound (200mg, 10%), a kind of oil of yellow by silicon column chromatography (hexane/EtOAc, 6:1).
1H NMR(500MHz,CDCl
3)δ1.76(3H,brs),1.83(3H,brs),3.42(2H,d,J＝7.0Hz),5.10(2H,s),5.27(1H,t,J＝7.0Hz),6.40(2H,d,J＝8.0Hz),6.94(1H,t,J＝8.5Hz)；ESIMS177[M-H]
-。
Preparation 2-(4-(trifluoromethyl) phenyl)-7-hydroxyl-8-(3-methyl but-2-ene base)-4H-benzopyran-4-one (compound 29).
By ethyl 4-trifluoromethyl benzoylacetic acid ester (420mg, 1.46mmol) and 2-(3-methyl but-2-ene base) benzene-1, the microwave for mixture (Biotage, temperature is controlled at 240 DEG C) of 3-glycol (130mg, 0.73mmol) irradiates 30 minutes.Obtain target compound (90mg, 40%), a kind of white solid by silicon column chromatography (hexane/EtOAc, 1:2) purifying work in-process.
1HNMR(500MHz,DMSO-d
6)δ1.64(3H,brs),1.79(3H,s),3.60(2H,d,J＝7.0Hz),5.25(1H,t,J＝7.0Hz),7.02(1H,d,J＝9.0Hz),7.04(1H,s),7.79(1H,d,J＝9.0Hz),7.96(2H,d,J＝8.5Hz),8.26(2H,d,J＝8.0Hz),10.76(1H,s)；ESIMS375[M+H]
+。
Preparation 7-hydroxyl-8-(3-methyl but-2-ene base)-2-(4-aminomethyl phenyl)-4H-benzopyran-4-one (compound 30)
By with the similar approach synthesising target compound of preparing compound 2-(4-(trifluoromethyl) phenyl)-7-hydroxyl-8-(3-methyl but-2-ene base)-4H-benzopyran-4-one, a kind of white solid (65mg, 28%).
1H NMR(500MHz,DMSO-d
6)δ1.64(3H,s),1.79(3H,s),2.40(3H,s),3.59(2H,d,J＝6.5Hz),5.28(1H,m),6.84(1H,s),6.99(1H,d,J＝9.0Hz),7.40(2H,d,J＝8.0Hz),7.76(1H,d,J＝9.0Hz),7.94(2H,d,J＝8.5Hz),10.68(1H,s)；
13C NMR(125MHz,DMSO-d
6)δ17.9,21.0,21.9,25.4,105.7,114.0,115.1,116.3,121.9,123.4,126.0(2C),128.8,129.7(2C),131.5,141.7,155.1,159.8,162.0,176.7；ESIMS321[M+H]
+。
Preparation 2-(4-fluorophenyl)-7-hydroxyl-8-(3-methyl but-2-ene base)-4H-benzopyran-4-one (compound 31)
By with the similar method synthesising target compound of method of preparing compound 2-(4-(trifluoromethyl) phenyl)-7-hydroxyl-8-(3-methyl but-2-ene base)-4H-benzopyran-4-one, a kind of white solid (68mg, 30%).
1H NMR(500MHz,DMSO-d
6)δ1.64(3H,s),1.78(3H,s),3.59(2H,d,J＝7.0Hz),5.24(1H,m),6.90(1H,s),6.99(1H,d,J＝8.5Hz),7.43-7.46(2H,m),7.77(1H,d,J＝8.5Hz),8.09-8.12(2H,m),10.70(1H,s)；
13C NMR(125MHz,DMSO-d
6)δ17.9,21.9,25.4,106.3,114.1,115.1,116.2(d,J＝21.5Hz),121.9,123.5,128.2,128.7(d,J＝8.6Hz),131.6,155.2,159.9,161.0,163.9(d,J＝248.9Hz),176.7；ESIMS325[M+H]
+。
Preparation 2-(3-(tetrahydrochysene-2H-pyrans-2-base oxygen base) phenoxy group)-tetrahydrochysene-2H-pyrans (compound 32).
By the mixture stirring and refluxing of Resorcinol (11g), DCM (100mL) and PPTS (1g) after 10 minutes, slowly add 3,4-dihydro-2H-pyrans (16.8g), then mixture is stirred 3 hours at ambient temperature.The solution obtaining is concentrated, obtain target compound (22g, 80%), a kind of white solid by flash chromatography.
1h NMR (300MHz, CDCl
3): δ 7.20 (t, 1H), 6.85 (t, 3H), 5.40 (s, 2H), 3.60-4.00 (t, 4H), 1.60-2.10 (t, 12H); LCMS[M+H]
+: 279; Purity (LCMS) >95%.
Preparation 2-(2-(3-methyl but-2-ene base)-3-(tetrahydrochysene-2H-pyrans-2-base oxygen base) phenoxy group)-tetrahydrochysene-2H-pyrans (compound 33)
Under the condition of 0 DEG C and nitrogen protection, in the cyclohexane solution of the 200mL that contains 2-(3-(tetrahydrochysene-2H-pyrans-2-base oxygen base) phenoxy group)-tetrahydrochysene-2H-pyrans (12g), add the n-Butyl Lithium of 17mL.Compound of reaction is refluxed 3 hours, cooling after, add the bromo-3-methyl-2-butene of 1-(8g), the reactant that obtains is refluxed 3 hours.After cooling, dilute with the water of 200mL, with EtOAc extraction, obtain target compound (10g, 60%), a kind of oily mater by purified by flash chromatography.
1h NMR (300MHz, CDCl
3): δ 6.70-7.20 (t, 3H), 5.45 (s, 2H), 5.25 (s, 1H), 3.60-4.00 (t, 4H), 3.45 (s, 1H), 1.80 (s, 6H), 1.60-2.10 (t, 12H); LCMS[M+H]
+: 347; Purity (LCMS) >95%.
Preparation 2-(3-methyl but-2-ene base) benzene-1,3-glycol (compound 34).
By compound 33 (10g), methyl alcohol (250mL), oxalic acid (15g) and water (40mL) mix and blend 1 hour at ambient temperature.The mixture obtaining is concentrated in a vacuum, obtain target compound (6g, 95%), a kind of liquid material by purified by flash chromatography.
1h NMR (300MHz, CDCl
3): δ 6.98 (m, 1H), 6.41 (d, 2H), 5.27 (m, 1H), 5.10 (s, 2H), 3.43 (d, 2H), 1.80 (d, 6H), LCMS[M+H]
+: 194; Purity (LCMS) >93%.
Prepare ethyl 3-carbonyl-3-(pyridin-4-yl) propionic ester (compound 35).
By ethyl iso-nicotinate (3.02g), EtOAc (10mL) and sodium hydride (60%, 0.53g) Hybrid Heating refluxes 3 hours, cooling rear water (20mL) dilution, carries out acidifying with citric acid (5%).Be extracted with ethyl acetate water, use normal saline washing organic extract, by dried over mgso, filter and concentrate and obtain compound 35 (3.5g, 85%), a kind of solid state material in a vacuum.
1hNMR (300MHz, DMSO): δ 8.40 (d, 2H), 7.58 (d, 2H), 5.03 (S, 2H), 3.93 (t, 2H), 1.14 (t, 3H), LCMS[M+H]
+: 179; Purity (LCMS) >93%.
Preparation 7-hydroxyl-8-(3-methyl but-2-ene base)-2-(pyridin-4-yl)-4H-benzopyran-4-one (compound 36).
Compound 34 (3.00g), compound 35 (3.00g) and 1-phenoxy group benzene (30mL) Hybrid Heating are refluxed 50 minutes, after cooling, obtain compound 36 (300mg, 6%), a kind of solid state material by purified by flash chromatography.
1h NMR (300MHz, DMSO): δ 10.81 (s, 1H), 8.82 (d, 2H), 8.00 (d, 2H), 7.80 (d, 2H), 7.13 (s, 1H), 7.00 (d, 1H), 5.25 (d, 1H), 3.61 (d, 2H), (1.640-1.79 d, 6H), LCMS[M+H]
+: 308; Purity (HPLC) >97%.
Prepare ethyl 3-carbonyl-3-(pyridin-3-yl) propionic ester (compound 37).
Nikithan (2.26g), EtOAc (20mL) and sodium ethylate (11.4g) Hybrid Heating are refluxed 16 hours.In reaction mixture, add water (20mL).With hydrochloric acid, acidified aqueous solution being become to pH value is 6, extracts with ether.Remove in a vacuum solvent and obtain brown oil, obtain compound 37 (1.01g, 52%) by column chromatography (2:1, hexane-EtOAc) purifying.
1h NMR (300MHz, DMSO): δ 8.90-9.10 (d, 1H), 8.20-8.80 (d, 1H), 8.00-8.25 (d, 1H), 7.30-7.40 (d, 1H), 4.26 (s, 2H), 1.30 (t, 3H), LCMS[M+H]
+: 179; Purity (LCMS) >93%.
Preparation 7-hydroxyl-8-(3-methyl but-2-ene base)-2-(pyridin-3-yl)-4H-benzopyran-4-one (compound 38).
Compound 34 (3.00g), compound 37 (3.00g) and 1-phenoxy group benzene (30mL) Hybrid Heating are refluxed 30 minutes.Question response mixed solution is cooled to after room temp, is purified and is obtained compound 38 (200mg, 4%), a kind of yellow solid by flash chromatography.
1h NMR (300MHz, DMSO): δ 10.76 (s, 1H), 9.21 (s, 1H), 8.76 (d, 1H), 8.41 (d, 2H), 7.76 (d, 1H), 7.62 (d, 1H), 7.00 (t, 2H), 5.24 (d, 1H), 3.57 (d, 2H), 1.40-1.70 (d, 6H), LCMS[M+H]
+: 308; Purity (HPLC) >97%.
+.
The method of test organisms activity
The activity of the compound of formula of the present invention (I) can be passed through following analytic explanation.
The expression of ER-α varient in human breast cancer sample
Bought a film of smearing in advance mankind mastopathy cell's tissue from place of ProSci Incorporated (Poway, CA) company.With can anti-ER-α 36 antibody of explicit recognition ER-α 36 and the second antibody of HRP mark detect film, re-use enhanced chemiluminescence (ECL) detection reagent (Amersham Pharmacia Biotech company provides) and make it to manifest.Mark on this same film of wash-out, then with identifying three types ER-α, estrogen antagonist acceptor-Alpha antibodies the H222 (Novocastra Laboratories Ltd, UK company provides) that is ER-α 66, ER-α 46 and ER-α 36 detects film.Fig. 1 shows that ER-α 66, ER-α 46 and ER-α 36 do not express in common mammary tissue (1 road), but in the sample (5 road) of the sample (2 road) of infitrating ductal carcinoma, infiltrating lobular carcinoma and non-infiltration duct carcinoma (7 road), expresses.In addition, ER-α 36 expresses in another sample (6 road) of aggressive duct carcinoma (4 road) and infitrating ductal carcinoma.The infitrating ductal carcinoma that is positioned at 2 and 3 roads comes from respectively two different patients.The infitrating ductal carcinoma that is positioned at 5 and 6 roads also comes from respectively two different patients.This result shows, ER-α 36 does not express in common mammary tissue, and expresses in the ER-negative breast cancer sample of not expressing ER-α 66 and ER-α 46.
The expression of ER-α 36 in ER-negative breast cancer clone MDA-MB-231
MDA-MB-231 is that the clone of a kind of disappearance ER-α 66 that everybody knows and ER-α 46 is (referring to Relevanceof breast cancer cell lines as models for breast tumours:an update.Marc Lacroix, Guy Leclercq, Breast Cancer Research and Treatment83:249-289 (2004)).Locate to obtain MDA-MB-231 cell from U.S.'s cell strains storehouse (ATCC).MDA-MB-231 cell is placed on containing the 8 hole BIOCOAT chamber slides (BD Science Discovery Labware company provides) of the foetal calf serum of Dulbecco ' s Modified Eagle ' s Medium (DMEM) and 10% upper, under the condition of the carbonic acid gas containing 5% and 37 DEG C, cultivates 12 hours.Then use phosphate buffered saline buffer (PBS) to rinse cell twice, add paraformaldehyde fixed cell in PBS (pH7.4) of 4%, and place at ambient temperature 30 minutes.Afterwards, rinse cell with PBS, with the penetrating rupture of membranes of 0.5% (v/v) Triton X-100 10 minutes.Again rinse cell with PBS, add the PBS containing 3% serum, and place at ambient temperature 1 hour.On slide, add ER-α 36 specific antibodies, or add in advance and the same antibody that can cultivate in conjunction with the immunogen peptide of ER-α 36 specific antibodies 30 minutes, cultivate at ambient temperature 1 hour, then rinse 3 times with the PBS (PBST) that contains 0.5%Triton X-100, then use the second antibody of fluorescein isothiocyanate (FITC) mark to cultivate.Finally, rinse slide 3 times with PBST, with PBS flushing 1 time, add again immunofluorescence label (Molecular Probes, Eugene, OR company provides), under the microscope of Nikon E600 model, observe, obtain image by MRC-1024 copolymerization imaging system (Bio-Rad company provides).Fig. 2 shows that MDA-MB-231 cell is positive by ER-α 36 antibody stainings.The same antibody of being crossed by immunogen peptide preculture does not demonstrate any dyeing, shows the specificity of this antibody.
Analyze the effect that the apoptosis of ER-negative breast cancer MDA-MB-231 cell is produced
The foetal calf serum that MDA-MB-231 cell is placed in to DMEM and 10% under 37 DEG C and 5% carbon dioxide conditions, cell density is with 1x10 on every 60-mm ware
5individual cell.With being dissolved in the test compound processing MDA-MB-231 cell that DMSO concentration is 0 μ M, 1 μ M, 5 μ M and 10 μ M, the time is a week.Under Nikon TS100 inverted microscope, observe the cell of processing, take its metamorphosis.
Analyze the effect that the apoptosis of ER-positive breast cancer MCF7 cell is produced
MCF7 clone be a kind of can high efficient expression ER-α 66, ER-α 46 and the breast cancer cell line of ER-α 36 (referring to Relevance of breast cancer cell lines as models for breast tumours:an update.Marc Lacroix, GuyLeclercq, Breast Cancer Research and Treatment (2004) 83,249-289; Wang et al., Proc.Natl.Acad.Sci.U.S.A.103:9063-9068 (2006)).Under 37 DEG C and 5% carbon dioxide conditions, the MCF7 cell obtaining is kept in the DMEM/F12 substratum (Invitrogen company provides) that contains 10% foetal calf serum from ATCC place.Process MCF7 cell by concentration at the test-compound 6,8,14,22,27,29,30,31,36 and 38 of 1M to 25M, test the impact of these compounds on MCF7 Growth of Cells, the time is 10 days.Control group uses MCF7 not having test compound to add, and in the identical situation of other condition, analyzes.Under Nikon TS100 inverted microscope, observe the cell of processing, take its metamorphosis.Table 1 has shown analytical test result.
The apoptosis analysis of table 1. to ER-positive breast cancer MCF7 cell
The MCF7 cell of overexpression ER-α 36 and the apoptosis of the MCF7 cell with tamoxifen resistance are detected
The MCF7 cell of overexpression ER-α 36 is by ER-α 36 expression vectors being stably transfected in MCF cell and prepare.ER-α 36 expression vectors be by the cDNA segment of the 1.1-kb ER-α 36 in pBluescript plasmid is cloned into mammalian expression vector pCB6+ builds (referring to people such as Wang, BBRC, 336:1023-1027 (2005)).ER-α 36 expression vectors that build contain cytomegalovirus (CMV) early promoter.Use FuGene6 transfection reagent (Roche Molecular Biochemicals company provides) by ER-α 36 expression vector transfections to MCF7 cell.After transfection 48 hours, again cell is placed and cultivated, and screened for 2 week with the G418 (Invitrogen company provides) of 500 μ g/ml, until there is clone body.Clone body is collected together to cultivation, confirms the expression of ER-α 36 by antibody labeling analysis.
The MCF7 cell with tamoxifen resistance is by MCF7 cell is cultivated and generated for 3 months in the substratum that contains tamoxifen.By the MCF7 cell harvesting of still surviving after 3 months together, continue to cultivate as the MCF7 cell with tamoxifen resistance.Then carry out antibody labeling analysis, to find out the cell of highly expressing ER-α 36.
Under 37 DEG C and 5% carbon dioxide conditions, clone is kept in the DMEM/F12 substratum that contains 10% foetal calf serum.By cell to have 1x10 in every 100-mm
5the density of individual cell is put into culture dish, processes cell two weeks with the test compound that concentration is 0 to 10 μ M.Calculate the quantity of survivaling cell after two weeks.Each concentration point needs to calculate the cell quantity of 5 culture dish.
Body inner analysis
Suppress the efficiency of the interior ER-positive of nude mouse and ER-negative breast cancer growth of xenografted
Test compound is dissolved in Semen Maydis oil (20mg/mL).Solution is preserved under 4 DEG C of conditions, prepares for animals administer.Be filling food mode to the administering mode of nude mice.
The formation of analyzing and testing tumour in the female nude mice in 6 week age.Be 1 × 10 by concentration
7200 μ l Matrigel solution (BD Biosciences company provides) of individual MCF7 cell or MDA-MB-231 cell are injected in the mammary fat pad of nude mice.Every kind of breast cancer cell is injected in respectively on the same group in 5 nude mouses.Within 1.7mg/60 days, discharge E2 β piller (piller of a kind of slow release E2 β that can discharge a certain amount of E2 β continuous 60 day every day) subcutaneous implantation, after 5 days, inoculate MCF7 cell.Use feeding animal pin that the test compound being dissolved in Semen Maydis oil is injected with diameter in the animal body for 0.5cm tumour.5mg test compound is injected to every nude mice that inoculates MCF7 cell, every other day inject once continuous 15 days.Nude mice to every inoculation MDA-MB-231 cell is injected 5mg test compound, every other day injects once continuous 30 days.Determine by Palpation whether tumour disappears, and every other day all with vernier caliper measurement and take two mutually perpendicular diameter and monitor the size of tumour.
Suppress the efficiency of human breast cancer BCAP-37 Transplanted cells knurl growth in nude mouse
With test compound 5,6,8,14,22,36 and 38 treatments are with the nude mice of breast cancer transplantable tumor, to test the effect of their inhibition tumor growths.Extract tumor tissues from having in the nude mouse of BCAP-37 cell, cut into pieces.Several tumor tissues are implanted to the oxter of female nude mice right fore.After implantation, within continuous 6 days, once a day it is injected to E2 β solution with the dosage of every nude mice 7 μ g, to stimulate tumour in the growth of being noted in mouse body.Since the 7th day, to nude mice injection 35mg/kg test compound.Use tamoxifen as positive control.Use sweet oil as negative control.Test compound is dissolved in olive oil solution (20mg/mL).Continuous 15 day every day is to test compound and the tamoxifen of nude mice administration 35mg/kg, or sweet oil.After nude mice death, to its dissection and take out tumor tissues and weigh.Growth inhibition ratio with following formula percentage calculation tumor tissues: the weight in average of the growth inhibition ratio of tumour=(weight in average of negative control group exemplary embodiment lock-test compound tumour for the treatment of)/negative control group tumour.Following table 2 has shown experimental result.
Table 2. test compound suppresses the efficiency of human breast cancer BCAP-37 cell growth in vivo
| Compound | The growth inhibition ratio (%) of tumour |
| Negative control group | 0 |
| Tamoxifen | 40-50 |
| Compound 5 | 26 |
| Compound 6 | 44 |
| Compound 8 | 62 |
| Compound 14 | 37 |
| Compound 22 | 66 |
| Compound 36 | 56 |
| Compound 38 | 24 |
Suppress the efficiency of cervical cancer U14 Transplanted cells knurl growth in ICR mouse body
From the ICR mouse that contains cervical cancer U14 clone, 5ml peritoneal fluid is extracted in abdominal cavity out.Ratio with 1:5 dilutes peritoneal fluid with salt solution.By oxter and the breast of the right fore of the female ICR mouse of the subcutaneous injection of peritoneal fluid of 0.2ml dilution.After implantation, at once respectively with test compound, tamoxifen and sweet oil treatment ICR mouse.Within continuous 14 days, once a day ICR mouse is injected test compound, tamoxifen or the sweet oil of various dose.After mouse death, it is dissected to taking-up tumor tissues and weigh.The test of every kind of test compound and dosage is all used 10 female ICR mouse.Calculate and compare the inhibition rate of tumor growth of the ICR mouse that test compound, tamoxifen and sweet oil processed.
Claims (10)
1. following formula (I) compound:
2. compound as claimed in claim 1, this compound is for the relevant disease of abnormal cell proliferation of preventing or treatment is relevant with ER-α to main body.
3. compound as claimed in claim 1, wherein said main body is Mammals.
4. compound as claimed in claim 3, wherein said Mammals is people.
5. compound as claimed in claim 1, wherein said compound is by comprising oral cavity, mucous membrane, hypogloeeis, eyes, rectum, brain pond, vagina, peritonaeum, bladder or nasal administration.
6. compound as claimed in claim 2, wherein said disease is selected from following group: mammary cancer, colorectal carcinoma, liver cancer, lung cancer, myelomatosis cancer, ovarian cancer, prostate cancer, uterus carcinoma or osteoporosis.
7. compound as claimed in claim 2, wherein said disease is mammary cancer.
8. compound as claimed in claim 2, wherein said disease is liver cancer.
9. compound as claimed in claim 2, wherein said disease is lung cancer.
10. compound as claimed in claim 2, wherein said disease is osteoporosis.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US12/558,392 US20100016352A1 (en) | 2008-04-18 | 2009-09-11 | Compounds and methods for treating estrogen receptor-related diseases |
| US12/558,392 | 2009-09-11 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200910180487.5A Division CN102018698B (en) | 2008-04-18 | 2009-10-16 | Compounds and methods for treating estrogen receptor-related diseases |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103965172A true CN103965172A (en) | 2014-08-06 |
Family
ID=50545514
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410190543.4A Pending CN103965173A (en) | 2009-09-11 | 2009-10-16 | Compound and method for treating estrogen receptor-related diseases |
| CN201310705589.0A Pending CN103755673A (en) | 2009-09-11 | 2009-10-16 | Compound and method for treating estrogen receptor-related diseases |
| CN201410189817.8A Pending CN103965172A (en) | 2009-09-11 | 2009-10-16 | Compound and method for treating estrogen receptor-related diseases |
Family Applications Before (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410190543.4A Pending CN103965173A (en) | 2009-09-11 | 2009-10-16 | Compound and method for treating estrogen receptor-related diseases |
| CN201310705589.0A Pending CN103755673A (en) | 2009-09-11 | 2009-10-16 | Compound and method for treating estrogen receptor-related diseases |
Country Status (1)
| Country | Link |
|---|---|
| CN (3) | CN103965173A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104940189B (en) * | 2014-08-31 | 2019-01-11 | 北京罗诺强施医药技术研发中心有限公司 | The composition for treating hyperplasia disease |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1147976A (en) * | 1965-12-21 | 1969-04-10 | Fisons Pharmaceuticals Ltd | Chromone derivatives |
| WO2001016127A1 (en) * | 1999-09-01 | 2001-03-08 | Takeda Chemical Industries, Ltd. | Chromone derivatives, process for the preparation of the same and uses thereof |
| US20030108629A1 (en) * | 2001-07-17 | 2003-06-12 | Chou Wen Hsien | Compositions and methods for prostate and kidney health and disorders, an herbal preparation |
| US6750248B2 (en) * | 2001-11-09 | 2004-06-15 | National University Of Singapore | Methods for preparing an estrogenic preparation and isolated estrogenic compounds from a plant and uses thereof |
| US8138165B2 (en) * | 2002-10-22 | 2012-03-20 | Jenken Biosciences, Inc. | Chromones and chromone derivatives and uses thereof |
| CN101528038B (en) * | 2006-10-25 | 2011-05-11 | 盛诺基医药科技有限公司 | Compounds and methods for treating estrogen receptor-related diseases |
| CN101104611A (en) * | 2007-04-29 | 2008-01-16 | 殷正丰 | 3-methoxylflavonoid compound, preparation method and application thereof |
-
2009
- 2009-10-16 CN CN201410190543.4A patent/CN103965173A/en active Pending
- 2009-10-16 CN CN201310705589.0A patent/CN103755673A/en active Pending
- 2009-10-16 CN CN201410189817.8A patent/CN103965172A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| CN103965173A (en) | 2014-08-06 |
| CN103755673A (en) | 2014-04-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102018698B (en) | Compounds and methods for treating estrogen receptor-related diseases | |
| CN102558164B (en) | Benzofurantone estrogenic agents | |
| JP5265556B2 (en) | Compounds and methods for treating estrogen receptor related diseases | |
| CN103204838B (en) | The synthesis of polyhydroxy Benzofurantone compound and its antitumor action | |
| JP5938400B2 (en) | Pyrrolyl-substituted dihydroindol-2-one derivatives, preparation methods and uses thereof | |
| CN105008343A (en) | Benzothiophene derivatives and compositions thereof as selective estrogen receptor degraders | |
| CN101146798A (en) | Novel heterocyclic benzo[C]chromene derivatives useful as modulators of the estrogen receptors | |
| CN102753564B (en) | 6 substituted derivatives of estradiol and its using method | |
| CN105980372A (en) | Functionalised benzopyran compounds and use thereof | |
| CN108349959A (en) | The coumarin derivative and its preparation method and application of 4 substitutions | |
| CN110240587A (en) | A kind of aryl difluorobenzyl ether compound, Preparation method and use | |
| CN106565685A (en) | Tubulin inhibitor | |
| CN103965172A (en) | Compound and method for treating estrogen receptor-related diseases | |
| CN109180649A (en) | A kind of IDO inhibitor and preparation method thereof containing indole ring | |
| CN111170980B (en) | Calycosin derivative and synthesis method and application thereof | |
| CN102268014B (en) | Condensed heteroaryl derivative and its preparation method and use | |
| CN108186630B (en) | Application of isatin analogue in preparation of antitumor drugs | |
| CN115843271A (en) | Indole derivatives and their use for the treatment of cancer | |
| WO2020098516A1 (en) | Use of 4-(benzothiazole-2-yl)arylamine compound in treating stomach cancer | |
| CN102171215B (en) | 7H-imidazo[1, 2-a]pyrano[2, 3-c]pyridine derivations and the use thereof | |
| KR20100004681A (en) | Use in anti-cancer agent of 5,4'-dimethoxyflavone showing regulatory effect on p21 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20151028 Address after: 100000 A201 room, No. 5, Pioneer Road, Beijing, Haidian District Applicant after: Beijing Shengnuoji Medicine Technology Co., Ltd. Address before: Chinese Hongkong Hennessy Road No. 4 first Insurance Mansion 8 buildings B room and C room Applicant before: Shenogen Pharma Group Ltd. |
|
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20140806 |