CN1469743A - Estrogen receptor modulators - Google Patents
Estrogen receptor modulators Download PDFInfo
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- CN1469743A CN1469743A CNA018176720A CN01817672A CN1469743A CN 1469743 A CN1469743 A CN 1469743A CN A018176720 A CNA018176720 A CN A018176720A CN 01817672 A CN01817672 A CN 01817672A CN 1469743 A CN1469743 A CN 1469743A
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Abstract
The present invention relates to compounds and derivatives thereof, their synthesis, and their use as estrogen receptor modulators. The compounds of the instant invention are ligands for estrogen receptors and as such may be useful for treatment or prevention of a variety of conditions related to estrogen functioning including: bone loss, bone fractures, osteoporosis, cartilage degeneration, endometriosis, uterine fibroid disease, hot flashes, increased levels of LDL cholesterol, cardiovascular disease, impairment of cognitive functioning, cerebral degenerative disorders, restinosis, gynacomastia, vascular smooth muscle cell proliferation, obesity, incontinence, and cancer, in particular of the breast, uterus and prostate.
Description
Background of invention
Naturally occurring and synthetic estrogen has the wide range of therapeutic purposes, comprising: alleviate menopause syndrome, treatment acne, treatment dysmenorrhea and dysfunction temper palace is hemorrhage, treatment osteoporosis, treatment hirsutism, treatment carcinoma of prostate, treatment hot flush and angiocardiopathy preventing.Because estrogen has therapeutic value, find that therefore the chemical compound of simulation estrogen-like effects in estrogen response tissue is very interesting.
For example, the estrogen-like chemical compound will be of value to treatment and the loss of prevention bone.The bone loss occurrence in colony widely, comprise after the menopause or carried out uterectomy the women, used or using the patient of corticosteroid hormone treatment and had the patient of dysgenesia.The hypercalcemia that at present osteopathia of public's major concern is an osteoporosis, malignant tumor is relevant, shift the osteoporosis that erosion around the joint of the osteopenia that causes, periodontal, thyroid function surplus, rheumatic arthritis, Paget, the fixing osteopenia that causes and glucocorticoid cause by bone.All to be feature by the unbalanced bone loss that causes between bone resorption (being disintegrate) and the bone formation, the bone loss continues between the whole vital stage with the Mean Speed in every year about 14% all these diseases.But the speed that bone upgrades is complied with different positions and difference, and for example the bone of the alveolar bone of the trabecular bone of vertebra and narrow orifice upgrades the bone renewal faster than the cortex of long bone.Bone loss may be upgraded directly relatedly with bone, and the loss of the bone of vertebra can reach more than 5% every year after the menopause just, and menopause is the disease that causes fracture risk to increase.
In the U.S., 20 million peoples that have an appointment at present suffer from the detectability vertebral fracture that produces because of osteoporosis.In addition, 250,000 people that have an appointment every year suffer from the hip fracture that produces because of osteoporosis.This clinical manifestation is relevant with beginning 12% mortality rate in two years, and 30% patient needs the private home nursing after fracture.
Only in the U.S., osteoporosis just influences about 20-25 1,000,000 postmenopausal women.Now set up a kind of like this theory, promptly the quick loss of sclerotin is because ovary stops to produce estrogen among these women.Because research shows, the osteopenia that estrogen has slowed down and caused owing to osteoporosis, so controversies in hormone replacement in the elderly is considered to the Therapeutic Method of postmenopausal osteoporosis.
Beyond the deossification, estrogen also shows the influence to cholesterol biosynthesis and cardiovascular health.According to statistics, basic identical in the incidence rate of postmenopausal women and male centre's angiopathy; And the women has the cardiovascular disease incidence rate more much lower than the male before the menopause.Because the postmenopausal women lacks estrogen, therefore it is believed that estrogen plays a part useful in angiocardiopathy preventing.This mechanism is not fully aware of, can raise low density lipoprotein, LDL in the liver (LDL) cholesterol receptor but evidence shows estrogen, to remove excessive cholesterol.
The lipid level of accepting the postmenopausal women of controversies in hormone replacement in the elderly returns to the level suitable with premenopausal state.Therefore, controversies in hormone replacement in the elderly can effectively be treated this class disease.But with the application of this alternative medicine of having used relevant side effects limit of long-term estrogen.
Other disease that influences the postmenopausal women comprises estrogen-dependent breast carcinoma and uterus carcinoma.The estrogen antagonist chemical compound, the chemotherapy that has been widely used as treating the patient with breast cancer as tamoxifen.Tamoxifen, a kind of is the antagonist and the agonist of estrogen receptor simultaneously, can treat estrogen-dependent breast carcinoma valuably.But use the treatment of tamoxifen not ideal enough, because the agonist effect of tamoxifen has strengthened its estrogen side effect of not expecting.For example, the tamoxifen of exciting estrogen receptor and other chemical compound are easy to increase the generation of cancerous cell in the uterus.Better therapy for this kind of treatment cancer will be the estrogen antagonist chemical compound that has negligible agonist character or do not have agonist character.
Though estrogen is of value to the treatment disease, for example bone loses, blood lipid level increases and cancer, and long-term estrin treatment is relevant with the multiple disease that increases of the danger that comprises uterus and carcinoma of endometrium.These and other side effect of controversies in hormone replacement in the elderly is that many women are unacceptable, has therefore limited its use.
Other schemes, for example progestogen and estrogen administering drug combinations have been proposed the danger of attempting in reducing cancer.But this class scheme causes the patient experience withdrawal hemorrhage, and this can not accept for many elderly womans.In addition.Estrogen and progestogen are united the useful cholesterol reduction effect that has weakened estrin treatment of using.In addition, the The Long-term Effect of progestogen therapy is on the knees of the gods.
Except the postmenopausal women, the male who suffers from carcinoma of prostate also has benefited from the estrogen antagonist chemical compound.Carcinoma of prostate often is an endocrine sensitivity; Androgen stimulates cultivates tumor growth, and androgen suppresses to delay tumor growth.Estrogenic using helps treatment of prostate cancer and control, because the estrogenic level that reduces promoting sexual gland hormone of using reduces the androgen level thus.
Have now found that estrogen receptor has two kinds of forms: ER α and ER β.Part differently is incorporated into this two kinds of forms, and various forms has the different tissues specificity of binding partner.Therefore, might exist ER α or ER β are had optionally chemical compound, give tissue specificity to a certain degree thus specific ligand.
This area needs to produce as the active responding of controversies in hormone replacement in the elderly but does not have the chemical compound of its side effect.Also need the different tissues of body is shown the estrogen-like chemical compound of selectively acting.
The compounds of this invention is the part of estrogen receptor, therefore can be used for treating or prevent the various indications relevant with estrogen function, comprise: bone loss, fracture, osteoporosis, cartilage degeneration, endometriosis, uterus fiber disease, hot flush, the rising of LDL cholesterol levels, cardiovascular disease, Cognitive function damage, brain degenerative disease, restenosis, gynecomastia, vascular smooth muscle cell proliferation, obesity, incontinence, and cancer, especially breast carcinoma, uterus carcinoma and carcinoma of prostate.
Summary of the invention
The present invention relates to the chemical compound and the officinal salt thereof of following formula:
R wherein
1, R
2, R
3And R
4Be selected from hydrogen, C independently of one another
1-5Alkyl, C
3-8Cycloalkyl, C
2-5Alkenyl, C
2-5Alkynyl, C
3-8Cycloalkenyl group, phenyl, heteroaryl, heterocyclic radical, CF
3, OR
6, halogen, C
1-5Alkylthio group, thiocyanogen, cyano group ,-CO
2H ,-COOC
1-5Alkyl ,-COC
1-5Alkyl ,-CONZ
2,-SO
2NZ
2With-SO
2C1
-5Alkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, phenyl, heteroaryl, heterocyclic radical can randomly be replaced by following group: C
1-5Alkyl, C
3-8Cycloalkyl, CF
3, phenyl, heteroaryl, heterocyclic radical ,-OR
6, halogen, amino, C
1-5Alkylthio group, thiocyanogen, cyano group ,-CO
2H ,-COOC
1-5Alkyl ,-COC
1-5Alkyl ,-CONZ
2,-SO
2NZ
2With-SO
2C
1-5Alkyl;
R
5Be selected from C
1-5Alkyl, C
3-8Cycloalkyl, C
2-5Alkenyl, C
2-5Alkynyl, C
3-8Cycloalkenyl group, phenyl, heteroaryl, heterocyclic radical, wherein said group can randomly be replaced by following groups: C
1-5Alkyl, C
3-8Cycloalkyl, CF
3, phenyl, heteroaryl, heterocyclic radical ,-OR
6, halogen, amino, C
1-5Alkylthio group, thiocyanogen, cyano group ,-CO
2H ,-COOC
1-5Alkyl ,-COC
1-5Alkyl ,-CONZ
2,-SO
2NZ
2With-SO
2C
1-5Alkyl;
X and Y are selected from oxygen, sulfur, sulfoxide and sulfone independently of one another;
R
6Be selected from hydrogen, C
1-5Alkyl, benzyl, methoxy, three Organosilyls, C
1-5Alkyl-carbonyl, alkoxy carbonyl group and CONZ
2
Each Z is independently selected from hydrogen, C
1-5Alkyl, trifluoromethyl, wherein said alkyl can randomly be replaced by following groups: C
1-5Alkyl, CF
3,-OR
6, halogen, amino, C
1-5Alkylthio group, thiocyanogen, cyano group ,-CO
2H ,-COOC
1-5Alkyl ,-COC
1-5Alkyl, CONV
2,-SO
2NV
2With-SO
2C
1-5Alkyl;
Perhaps the nitrogen that is connected with them of two Z can form 3-8 unit ring together, described ring can randomly comprise the atom that is selected from carbon, oxygen, sulfur and nitrogen, wherein said ring can be saturated or unsaturated, and the carbon atom of described ring can randomly be selected from following substituent group replacement: C by one to three
1-5Alkyl, CF
3,-OR
6, halogen, amino, C
1-5Alkylthio group, thiocyanogen, cyano group ,-CO
2H ,-COOC
1-5Alkyl ,-COC
1-5Alkyl ,-CONV
2,-SO
2NV
2With-SO
2C
1-5Alkyl;
Each V is independently selected from C
1-5Alkyl, CF
3,-OR
6, halogen, amino, C
1-5Alkylthio group, thiocyanogen, cyano group ,-CO
2H ,-COOC
1-5Alkyl ,-COC
1-5Alkyl and-SO
2C
1-5Alkyl;
Each n is the integer of 0-5 independently.
The invention still further relates to the pharmaceutical composition that comprises The compounds of this invention and pharmaceutically suitable carrier.
The invention still further relates to the method for preparation pharmaceutical composition of the present invention.
The invention still further relates to the method and the intermediate that are used to prepare The compounds of this invention and pharmaceutical composition.
The invention still further relates to the method that produces the estrogen receptor regulating action in the mammal of needs adjusting estrogen receptor, this method comprises uses chemical compound of the present invention and pharmaceutical composition.
The invention still further relates to the method that produces the estrogen receptor antagonism in the mammal that needs the antagonism estrogen receptor, this method comprises uses chemical compound of the present invention and pharmaceutical composition.The estrogen receptor antagonism can be ER α antagonism and ER β antagonism or blended ER α and ER β antagonism.
The invention still further relates to the method that produces the estrogen receptor agonism effect in the mammal of the exciting estrogen receptor of needs, this method comprises uses chemical compound of the present invention and pharmaceutical composition.The estrogen receptor agonism effect can be ER α agonism and ER β agonism or blended ER α and ER β agonism.
The invention still further relates to the method for in the patient of needs treatment or prevention and estrogen function diseases associated, treating or preventing described disease, described disease comprises: bone loss, fracture, osteoporosis, cartilage degeneration, endometriosis, uterus fiber disease, breast carcinoma, uterus carcinoma or carcinoma of prostate, hot flush, cardiovascular disease, Cognitive function damage, brain degenerative disease, restenosis, gynecomastia, vascular smooth muscle cell proliferation, obesity and incontinence, this method comprise uses chemical compound of the present invention and pharmaceutical composition.
The invention still further relates at needs and reduce the bone loss, reduce the LDL cholesterol levels and produce the method that produces required effect in the vasorelaxation action mammal, this method comprises uses chemical compound of the present invention and pharmaceutical composition.
Detailed Description Of The Invention
The present invention relates to chemical compound as estrogenic agents.Chemical compound of the present invention is described by following chemical formula:
R wherein
1, R
2, R
3And R
4Be selected from hydrogen, C independently of one another
1-5Alkyl, C
3-8Cycloalkyl, C
2-5Alkenyl, C
2-5Alkynyl, C
3-8Cycloalkenyl group, phenyl, heteroaryl, heterocyclic radical, CF
3, OR
6, halogen, C
1-5Alkylthio group, thiocyanogen, cyano group ,-CO
2H ,-COOC
1-5Alkyl ,-COC
1-5Alkyl ,-CONZ
2,-SO
2NZ
2With-SO
2C
1-5Alkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, phenyl, heteroaryl, heterocyclic radical can randomly be replaced by following group: C
1-5Alkyl, C
3-8Cycloalkyl, CF
3, phenyl, heteroaryl, heterocyclic radical ,-OR
6, halogen, amino, C
1-5Alkylthio group, thiocyanogen, cyano group ,-CO
2H ,-COOC
1-5Alkyl ,-COC
1-5Alkyl ,-CONZ
2,-SO
2NZ
2With-SO
2C
1-5Alkyl;
R
5Be selected from C
1-5Alkyl, C
3-8Cycloalkyl, C
2-5Alkenyl, C
2-5Alkynyl, C
3-8Cycloalkenyl group, phenyl, heteroaryl, heterocyclic radical, wherein said group can randomly be replaced by following groups: C
1-5Alkyl, C
3-8Cycloalkyl, CF
3, phenyl, heteroaryl, heterocyclic radical ,-OR
6, halogen, amino, C
1-5Alkylthio group, thiocyanogen, cyano group ,-CO
2H ,-COOC
1-5Alkyl ,-COC
1-5Alkyl ,-CONZ
2,-SO
2NZ
2With-SO
2C
1-5Alkyl;
X and Y are selected from oxygen, sulfur, sulfoxide and sulfone independently of one another;
R
6Be selected from hydrogen, C
1-5Alkyl, benzyl, methoxy, three Organosilyls, C
1-5Alkyl-carbonyl, alkoxy carbonyl group and CONZ
2
Each Z is independently selected from hydrogen, C
1-5Alkyl, trifluoromethyl, wherein said alkyl can randomly be replaced by following groups: C
1-5Alkyl, CF
3,-OR
6, halogen, amino, C
1-5Alkylthio group, thiocyanogen, cyano group ,-CO
2H ,-COOC
1-5Alkyl ,-COC
1-5Alkyl, CONV
2,-SO
2NV
2With-SO
2C
1-5Alkyl;
Perhaps the nitrogen that is connected with them of two Z can form 3-8 unit ring together, described ring can randomly comprise the atom that is selected from carbon, oxygen, sulfur and nitrogen, wherein said ring can be saturated or unsaturated, and the carbon atom of described ring can randomly be selected from following group replacement: C by one to three
1-5Alkyl, CF
3,-OR
6, halogen, amino, C
1-5Alkylthio group, thiocyanogen, cyano group ,-CO
2H ,-COOC
1-5Alkyl ,-COC
1-5Alkyl ,-CONV
2,-SO
2NV
2With-SO
2C
1-5Alkyl;
Each V is independently selected from C
1-5Alkyl, CF
3,-OR
6, halogen, amino, C
1-5Alkylthio group, thiocyanogen, cyano group ,-CO
2H ,-COOC
1-5Alkyl ,-COC
1-5Alkyl and-SO
2C
1-5Alkyl;
Each n is the integer of 0-5 independently.
In a compounds of the present invention, X is that oxygen and Y are sulfur.
In a compounds of the present invention, R
1, R
2, R
3And R
4Be selected from hydrogen, C
1-5Alkyl, C
3-8Cycloalkyl, C
1-5Alkenyl, C
1-5Alkynyl ,-OR
6And halogen.
In a compounds of the present invention, R
5Be selected from C
3-8Cycloalkyl, phenyl, heteroaryl and heterocyclic radical, wherein said group can be randomly by-OR
6Replace with halogen.
In a compounds of the present invention, R
6Be preferably selected from hydrogen, C
1-5Alkyl, benzyl, methoxy and triisopropyl silicyl.
The invention still further relates to the method for preparation I compound or its officinal salt,
R wherein
1Be H, F or Cl;
R
2Be H or OR
6
R
3Be H or OR
6
R
4Be H or CH
3
R
5Be C
1-5Alkyl, C
3-8Cycloalkyl, C
3-8Cycloalkenyl group, phenyl, heteroaryl or heterocyclic radical, wherein said group can randomly be replaced by following groups: C
1-5Alkyl, C
3-8Cycloalkyl, CF
3, phenyl, heteroaryl, heterocyclic radical ,-OR
6, halogen, amino, C
1-5Alkylthio group, thiocyanogen, cyano group, carboxyl (CO
2H), (alkoxymethyl)-2 acyl group (COOC
1-5Alkyl), carbonyl (COC
1-5Alkyl, formamido group (CONZ
2), sulfonamido (SO
2NZ
2) and sulfonyl (SO
2C
1-5Alkyl);
R
6Be H, benzyl, methyl, methoxy or triisopropyl silicyl, condition is to have OR when other places
6The time, it is chemically different;
X and Y are selected from oxygen, sulfur, sulfoxide and sulfone independently of one another;
Each Z is independently selected from hydrogen, C
1-5Alkyl, trifluoromethyl, wherein said alkyl can randomly be replaced by following groups: C
1-5Alkyl, CF
3,-OR
6, halogen, amino, C
1-5Alkylthio group, thiocyanogen, cyano group ,-CO
2H, COOC
1-5Alkyl ,-COC
1-5Alkyl ,-CONV
2,-SO
2NV
2With-SO
2C
1-5Alkyl;
Perhaps the nitrogen that is connected with them of two Z can form 3-8 unit ring together, described ring can randomly comprise the atom that is selected from carbon, oxygen, sulfur and nitrogen, wherein said ring can be saturated or unsaturated, and the carbon atom of described ring can randomly be selected from following group replacement: C by one to three
1-5Alkyl, CF
3,-OR
6, halogen, amino, C
1-5Alkylthio group, thiocyanogen, cyano group ,-CO
2H ,-COOC
1-5Alkyl ,-COC
1-5Alkyl ,-CONV
2,-SO
2NV
2And SO
2C
1-5Alkyl;
Each V is independently selected from C
1-5Alkyl, CF
3,-OR
6, halogen, amino, C
1-5Alkylthio group, thiocyanogen, cyano group ,-CO
2H ,-COOC
1-5Alkyl ,-COC
1-5Alkyl and-SO
2C
1-5Alkyl;
Each n is the integer of 0-5 independently;
And stereoisomer is a cis;
This method may further comprise the steps:
A) under alkali condition, with formula II chemical compound and the reaction of formula III chemical compound
Form formula IV chemical compound
B) in the presence of Reducing agent, under acid condition, the IV that cyclization step a obtains obtains the cis-compound of formula V
C) remove protecting group R
6, obtain the phenol of the replacement of formula VI
D) use reagent HO (CH
2)
nN (Z)
2The phenol of the replacement of the formula VI that alkylation step c obtains obtains formula I chemical compound
E) remove protecting group among the I that steps d obtains, obtain formula VIII chemical compound or formula IX chemical compound
F) remove VIII that step e obtains or remaining protecting group among the IX, obtain formula I chemical compound.
The invention still further relates to the method for preparation formula ID compound or pharmaceutically acceptable salt thereof
R wherein
1Be H, F or Cl;
R
3Be H;
R
4Be H or CH
3And
Stereoisomer is a cis; And
Optical isomer is dextral (+), its absolute configuration be (2S, 3R);
This method may further comprise the steps: a) under alkali condition, with formula IID chemical compound and the reaction of formula III D chemical compound
Form formula IVD chemical compound
B) in the presence of Reducing agent, under acid condition, the IVD that cyclization step a obtains obtains the cis-compound of formula VD
C) VD that obtains with step b carries out chiral chromatogram, to split enantiomer, obtains dextrorotation (+) isomer VID
D) dextrorotation (+) the isomer VID that uses 1-piperidines ethanol alkylation step c to obtain obtains formula VIID chemical compound
E) remove protecting group among the VIID that steps d obtains, obtain formula VIIID chemical compound or formula IXD chemical compound
F) remove VIIID that step e obtains or remaining protecting group among the IXD, obtain formula I chemical compound.
The invention still further relates to the method for preparation formula IE compound or pharmaceutically acceptable salt thereof
R wherein
1Be selected from H, F or Cl;
R
3And R
4Each is H naturally;
R
7Be selected from H or OH;
Its stereoisomer is a cis; And optical isomer is dextral (+), its absolute configuration be (2S, 3R);
This method may further comprise the steps: a) under alkali condition, with formula IIE chemical compound and the reaction of formula III E chemical compound
Form formula IVE chemical compound
B) in the presence of Reducing agent, under acid condition, the IVE that cyclization step a obtains obtains the raceme cis chemical compound of formula VE
C) optionally remove the protecting group of the VE that step b obtains, obtain the phenol of the replacement of formula VIE;
D) use the phenol of the replacement of the formula VIE that 1-piperidines ethanol alkylation step c obtains, obtain formula VIIE chemical compound
E) remove protecting group among the formula VIIE, obtain formula VIIIE chemical compound or formula IXE chemical compound
F) remove VIIIE that step e obtains or remaining protecting group among the IXE, obtain racemic I, g) I with racemic form splits, and is had (2S, 3R) dextrorotation (+) the isomer I of absolute configuration.
The invention still further relates to new being used to and prepare chemical compound of the present invention and compositions, be i.e. the intermediate of formula I, IA, IB, IC, ID and IE chemical compound.
One embodiment of the invention are intermediate of following formula:
Wherein
R
1Be H, F or Cl;
R
2Be H or OR
6
R
3Be H or OR
6
R
4Be H or CH
3
R
5Be C
1-5Alkyl, C
3-8Cycloalkyl, C
3-8Cycloalkenyl group, phenyl, heteroaryl or heterocyclic radical, wherein said group can randomly be replaced by following groups: C
1-5Alkyl, C
3-8Cycloalkyl, CF
3, phenyl, heteroaryl, heterocyclic radical ,-OR
6, halogen, amino, C
1-5Alkylthio group, thiocyanogen, cyano group, carboxyl (CO
2H), (alkoxymethyl)-2 acyl group (COOC
1-5Alkyl), carbonyl (COC
1-5Alkyl, formamido group (CONZ
2), sulfonamido (SO
2NZ
2) and sulfonyl (SO
2C
1-5Alkyl);
R
6Be H, benzyl, methyl, methoxy or triisopropyl silicyl, condition is to have OR when other places
6The time, it is chemically different;
Each Z is independently selected from hydrogen, C
1-5Alkyl, trifluoromethyl, wherein said alkyl can randomly be replaced by following groups: C
1-5Alkyl, CF
3,-OR
6, halogen, amino, C
1-5Alkylthio group, thiocyanogen, cyano group ,-CO
2H ,-COOC
1-5Alkyl ,-COC
1-5Alkyl ,-CONV
2,-SO
2NV
2With-SO
2C
1-5Alkyl;
Perhaps the nitrogen that is connected with them of two Z can form 3-8 unit ring together, described ring can randomly comprise the atom that is selected from carbon, oxygen, sulfur and nitrogen, wherein said ring can be saturated or unsaturated, and the carbon atom of described ring can randomly be replaced by following groups: C
1-5Alkyl, CF
3,-OR
6, halogen, amino, C
1-5Alkylthio group, thiocyanogen, cyano group ,-CO
2H ,-COOC
1-5Alkyl ,-COC
1-5Alkyl ,-CONV
2,-SO
2NV
2With-SO
2C
1-5Alkyl;
Each V is independently selected from C
1-5Alkyl, CF
3,-OR
6, halogen, amino, C
1-5Alkylthio group, thiocyanogen, cyano group ,-CO
2H ,-COOC
1-5Alkyl ,-COC
1-5Alkyl and-SO
2C
1-5Alkyl.
Another embodiment of the invention is the intermediate of following formula:
Wherein
R
1Be H, F or Cl;
R
2Be H or OR
6
R
3Be H or OR
6
R
4Be H or CH
3
R
5Be C
1-5Alkyl, C
3-8Cycloalkyl, C
3-8Cycloalkenyl group, phenyl, heteroaryl or heterocyclic radical, wherein said group can randomly be replaced by following groups: C
1-5Alkyl, C
3-8Cycloalkyl, CF
3, phenyl, heteroaryl, heterocyclic radical ,-OR
6, halogen, amino, C
1-5Alkylthio group, thiocyanogen, cyano group, carboxyl (CO
2H), (alkoxymethyl)-2 acyl group (COOC
1-5Alkyl), carbonyl (COC
1-5Alkyl, formamido group (CONZ
2), sulfonamido (SO
2NZ
2) and sulfonyl (SO
2C
1-5Alkyl);
R
6Be H, benzyl, methyl, methoxy or triisopropyl silicyl, condition is to have OR when other places
6The time, it is chemically different;
Each Z is independently selected from hydrogen, C
1-5Alkyl, trifluoromethyl, wherein said alkyl can randomly be replaced by following groups: C
1-5Alkyl, CF
3,-OR
6, halogen, amino, C
1-5Alkylthio group, thiocyanogen, cyano group ,-CO
2H ,-COOC
1-5Alkyl ,-COC
1-5Alkyl ,-CONV
2,-SO
2NV
2With-SO
2C
1-5Alkyl;
Perhaps the nitrogen that is connected with them of two Z can form 3-8 unit ring together, described ring can randomly comprise the atom that is selected from carbon, oxygen, sulfur and nitrogen, wherein said ring can be saturated or unsaturated, and the carbon atom of described ring can randomly be replaced by following groups: C
1-5Alkyl, CF
3,-OR
6, halogen, amino, C
1-5Alkylthio group, thiocyanogen, cyano group ,-CO
2H ,-COOC
1-5Alkyl ,-COC
1-5Alkyl ,-CONV
2,-SO
2NV
2And SO
2C
1-5Alkyl;
Each V is independently selected from C
1-5Alkyl, CF
3,-OR
6, halogen, amino, C
1-5Alkylthio group, thiocyanogen, cyano group ,-CO
2H ,-COOC
1-5Alkyl ,-COC
1-5Alkyl and-SO
2C
1-5Alkyl.
Another embodiment of the invention is the intermediate of following formula:
Wherein
R
1Be H, F or Cl;
R
6Be H, benzyl, methyl, methoxy or triisopropyl silicyl, condition is the R of all existence
6Group is chemically different.
Another embodiment of the invention is the intermediate of following formula:
Wherein
R
1Be H, F or Cl;
R
6Be H, benzyl, methyl, methoxy or triisopropyl silicyl, condition is the R of all existence
6Group is chemically different.
Another embodiment of the invention is the intermediate of following formula:
Wherein
R
1Be H, F or Cl;
R
2Be H or OR
6
R
3Be H or OR
6
R
4Be H or CH
3
R
5Be C
1-5Alkyl, C3-8 cycloalkyl, C3-8 cycloalkenyl group, phenyl, heteroaryl or heterocyclic radical, wherein said group can randomly be replaced by following groups: C
1-5Alkyl, C
3-8Cycloalkyl, CF
3, phenyl, heteroaryl, heterocyclic radical ,-OR
6, halogen, amino, C
1-5Alkylthio group, thiocyanogen, cyano group, carboxyl (CO
2H), (alkoxymethyl)-2 acyl group (COOC
1-5Alkyl), carbonyl (COC
1-5Alkyl, formamido group (CONZ
2), sulfonamido (SO
2NZ
2) and sulfonyl (SO
2C
1-5Alkyl);
R
6Be H, benzyl, methyl, methoxy or triisopropyl silicyl, condition is to have OR when other places
6The time, it is chemically different;
Each Z is independently selected from hydrogen, C
1-5Alkyl, trifluoromethyl, wherein said alkyl can randomly be replaced by following groups: C
1-5Alkyl, CF
3,-OR
6, halogen, amino, C
1-5Alkylthio group, thiocyanogen, cyano group ,-CO
2H ,-COOC
1-5Alkyl ,-COC
1-5Alkyl ,-CONV
2,-SO
2NV
2With-SO
2C
1-5Alkyl;
Perhaps the nitrogen that is connected with them of two Z can form 3-8 unit ring together, described ring can randomly comprise the atom that is selected from carbon, oxygen, sulfur and nitrogen, wherein said ring can be saturated or unsaturated, and the carbon atom of described ring can randomly be replaced by following groups: C
1-5Alkyl, CF
3,-OR6, halogen, amino, C
1-5Alkylthio group, thiocyanogen, cyano group ,-CO
2H ,-COOC
1-5Alkyl ,-COC
1-5Alkyl ,-CONV
2,-SO
2NV
2With-SO
2C
1-5Alkyl;
Each V is independently selected from C
1-5Alkyl, CF
3,-OR
6, halogen, amino, C
1-5Alkylthio group, thiocyanogen, cyano group ,-CO
2H ,-COOC
1-5Alkyl ,-COC
1-5Alkyl and-SO
2C
1-5Alkyl.
Another embodiment of the invention is the intermediate of following formula:
Wherein
R
1Be H, F or Cl;
R
6Be H, benzyl, methyl, methoxy or triisopropyl silicyl, condition is the R of all existence
6Be chemically different.
Another embodiment of the invention is the intermediate of following formula:
Wherein
R
1Be H, F or Cl;
R
6Be H, benzyl, methyl, methoxy or triisopropyl silicyl, condition is that the R6 of all existence is chemically different.
Limiting examples of the present invention comprises:
One embodiment of the invention are the methods that produce the estrogen receptor regulating action in the mammal that needs the estrogen receptor regulating action, and this method comprises any above-mentioned chemical compound or any above-mentioned pharmaceutical composition to administration treatment effective dose.
First kind embodiment is such method, and wherein the estrogen receptor regulating action is an antagonism.
The first group embodiment is such method, and wherein estrogen receptor is an ER α receptor.
The second group embodiment is such method, and wherein estrogen receptor is the ER beta receptor.
The 3rd group embodiment is such method, and wherein the estrogen receptor regulating action is blended ER α and ER beta receptor antagonism.
The second class embodiment is such method, and wherein the estrogen receptor regulating action is an agonism.
The first group embodiment is such method, and wherein estrogen receptor is an ER α receptor.
The second group embodiment is such method, and wherein estrogen receptor is the ER beta receptor.
The 3rd group embodiment is such method, and wherein the estrogen receptor regulating action is blended ER α and ER beta receptor agonism.
Another embodiment of the invention is the method for treatment or prevention mammal postmenopausal osteoporosis, and this method comprises any above-mentioned chemical compound or the pharmaceutical composition to the administration treatment effective dose of this treatment of need or prevention.
Another embodiment of the invention is the method for treatment or prevention mammal hysteromyoma, and this method comprises any above-mentioned chemical compound or the pharmaceutical composition to the administration treatment effective dose of this treatment of need or prevention.
Another embodiment of the invention is the method for treatment or prevention mammal restenosis, and this method comprises any above-mentioned chemical compound or the pharmaceutical composition to the administration treatment effective dose of this treatment of need or prevention.
Another embodiment of the invention is treatment or the endometriotic method of prevention mammal, and this method comprises any above-mentioned chemical compound or the pharmaceutical composition to the administration treatment effective dose of this treatment of need or prevention.
Another embodiment of the invention is the method for treatment or prevention mammal hyperlipemia, and this method comprises any above-mentioned chemical compound or the pharmaceutical composition to the administration treatment effective dose of this treatment of need or prevention.
The present invention of example is a pharmaceutical composition, and said composition comprises any above-mentioned chemical compound and pharmaceutically suitable carrier.The present invention of example makes up the pharmaceutical composition that makes by any above-mentioned chemical compound and pharmaceutically suitable carrier in addition.The present invention for example understands the method for pharmaceutical compositions, and this method comprises any above-mentioned chemical compound and pharmaceutically suitable carrier are combined.
To be any above-mentioned chemical compound treat and/or prevent application in the mammiferous osteoporotic medicine in preparation in the present invention of another example.To be any above-mentioned chemical compound treat and/or prevent application in the medicine of following disease in preparation in the present invention of another example: bone loss, bone resorption, fracture, cartilage degeneration, endometriosis, uterus fiber disease, breast carcinoma, uterus carcinoma, carcinoma of prostate, hot flush, cardiovascular disease, Cognitive function damage, brain degenerative disease, restenosis, vascular smooth muscle cell proliferation, incontinence and/or the disease relevant with estrogen function.
The invention still further relates to any above-mentioned chemical compound or pharmaceutical composition and one or more are used to prevent or treat the combination medicine of osteoporotic material.For example, chemical compound of the present invention can with other material of effective dose, for example organic diphosphonic acid salt or cathepsin K inhibitor administering drug combinations effectively.The limiting examples of described organic diphosphonic acid salt comprises alendronate, clodronate, etridronate salt, Ibandronate, incadronate, minodronate, neridronate, Risedronate, piridronate, pamldronate, Tiludronate, zoledronate, their officinal salt or ester and their mixture.Preferred organic diphosphonic acid salt comprises alendronate and officinal salt and mixture.Alendronate one sodium salt trihydrate most preferably.
The exact dose of diphosphate will change along with following factors: dosage regimen, selected concrete diphosphate oral tired, mammiferous age, size, sex and health status, sanatory character and seriousness and other relevant medical science and physical factors.Therefore accurate medicine effective quantity can't be determined in advance, but be easy to be determined by care-giver or clinicist.The amount that is fit to can adopt conventional experimental technique, is determined by animal model and people's clinical research.For obtaining the bone resorption inhibitory action, promptly use the diphosphate of bone resorption amount of suppression, select the diphosphate of suitable amount usually.For the people, effective oral dose of diphosphate is generally about 1.5 to about 6000 μ g/kg body weight, the about 2000 μ g/kg body weight of preferably about 10-.
For the human Orally administered composition that comprises alendronate, its officinal salt or its pharmaceutically acceptable derivant, unit dose generally comprises about 8.75mg to the alendronate chemical compound of about 140mg (in active alendronic acid weight, promptly in the weight of respective acids).
For medicinal application, the salt of chemical compound of the present invention is meant avirulent " officinal salt ".But other salt can be used for the preparation of The compounds of this invention or its officinal salt.When chemical compound of the present invention comprised basic group, the salt that term " officinal salt " comprises was meant avirulent salt, and they are generally by preparing free alkali and the organic acid or the inorganic acid reaction that are fit to.Representational salt includes, but are not limited to following: acetate, benzene sulfonate, benzoate, bicarbonate, disulfate, biatrate, borate, bromide, calcium salt, camsilate, carbonate, chloride, Clavulanate, citrate, dihydrochloride, edetate, ethanedisulphonate, Estolate, esilate, fumarate, gluceptate, gluconate, glutamate, Glu, the glycollyl p-aminophenyl hydrochlorate that swells, hexyl resorcin salt, hydrab amine, hydrobromate, hydrochlorate, hydroxynaphthoate, iodide, different thiosulfate, lactate, Lactobionate, laruate, malate, maleate, mandelate, mesylate, MB, methyl nitrate, Methylsulfate, mucate, naphthalene sulfonate, nitrate, N-methyl glucose ammonium salt, oleate, oxalates, embonate (pamoate), palmitate, pantothenate, phosphate/diphosphate, Polygalacturonate, Salicylate, stearate, sulfate, basic acetate, succinate, tannate, tartrate, teoclate (teoclate), toluene fulfonate, triethyl group iodate thing and valerate.In addition, when The compounds of this invention had acidic moiety, its officinal salt that is fit to can comprise alkali metal salt, as sodium or potassium salt; Alkali salt is as calcium or magnesium salt; And the salt that forms with the organic ligand that is fit to, as quaternary ammonium salt.
Chemical compound of the present invention can have chiral centre, therefore can exist with racemic modification, racemic mixture, non-enantiomer mixture and diastereomer monomer or enantiomeric form, the present invention includes all isomeric forms.Therefore, when chemical compound was chipal compounds, enantiomer isolating, that do not comprise other material basically was also included within the scope of the invention; The present invention also comprises all mixture of two kinds of enantiomer.The polymorph, hydrate and the solvate that also comprise The compounds of this invention in the scope of the invention.
The prodrug that comprises The compounds of this invention in the scope of the present invention.Usually, this class prodrug is the functional derivatives of The compounds of this invention, and they can easily be converted into required chemical compound in vivo.Therefore, in Therapeutic Method of the present invention, term administering or administration " comprise and use concrete disclosed chemical compound or specifically not disclosed but be converted into the described various indications of compounds for treating of described particular compound after using to the patient in vivo.Select and the conventional method of the prodrug derivant that preparation is fit to for example is described in " Design of Prodrugs ", H.Bundgaard edits, Elservier, and in 1985, the full text that is incorporated herein the document is as a reference.The metabolite of these chemical compounds comprises by The compounds of this invention being incorporated into the active substance that produces in the biotic environment.
Term " treatment effective dose " is meant biology or the medicine of medical response or the amount of medicament that causes research worker or tissue that the clinicist pursued, system, animal or human.
The term " bone resorption " that the present invention uses is meant the process of osteoclast degraded bone.
The term " alkali condition " that the present invention uses is meant and adds in reaction medium or use alkali.According to the Lowry-Bronsted definition, alkali is a kind of material of accepting proton; Perhaps according to the Lewis definition, alkali is that a kind of electron pair of supplying with is to form the material of covalent bond.The example of the alkali that the present invention uses is, but is not limited to, and tertiary amine is as triethylamine, diisopropyl ethyl amine etc.
The term " acid condition " that the present invention uses is meant and adds in reaction medium or use acid.According to the Lowry-Bronsted definition, acid is a kind of material of supplying with proton; Perhaps according to the Lewis definition, acid is that a kind of receivability electron pair is to form the material of covalent bond.The example of the acid that the present invention uses is, but is not limited to, and strong carboxylic acid is as trifluoroacetic acid etc.; Strong sulfonic acid is as trifluoromethanesulfonic acid etc.; And lewis acid, as boron trifluoride diethyl etherate thing, stannum dichloride etc.
The term " Reducing agent " that the present invention uses is meant the reagent that can carry out reduction reaction.Reduction reaction is the functional group of a kind or the reaction that intermediate is converted into the material of low classification.The example of the Reducing agent that the present invention uses is, but is not limited to, three organosilans or stannane, and as triethyl-silicane, triphenyl monosilane and three normal-butyl stannanes etc.
Term " chemically different " is meant two or more different R
6Substituent group, their unique texture is such, and promptly this area professional and technical personnel can select reaction condition, and this condition can be with a different R
6Substituent group is converted into hydrogen, but does not influence other R
6Group.
Term " alkyl " be meant by from the aliphatic saturated hydrocarbon of straight or branched, conceptually remove the substituted univalent perssad that a hydrogen atom obtains (promptly-CH
3,-CH
2CH
3,-CH
2CH
2CH
3,-CH (CH
3)
2,-CH
2CH
2CH
2CH
3,-CH
2CH (CH
3)
2,-C (CH)
3Deng).
Term " alkenyl " be meant by from the aliphatic unsaturated hydrocarbon of the straight or branched that comprises at least one two key, conceptually remove the substituted univalent perssad that a hydrogen atom obtains (promptly-CH=CH
2,-CH
2CH=CH
2,-CH=CHCH
3,-CH
2CH=C (CH
3)
2Deng).
Term " alkynyl " be meant by from the aliphatic unsaturated hydrocarbon of the straight or branched that comprises at least one three key, conceptually remove the substituted univalent perssad that a hydrogen atom obtains (promptly-CH ≡ CH ,-CH
2C ≡ CH ,-C ≡ CCH
3,-CH
2CH
2C ≡ CCH
3Deng).
Term " cycloalkyl " is meant by conceptually remove the substituted univalent perssad (being cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl or suberyl) that a hydrogen atom obtains from the saturated mono cyclic hydrocarbon.
Term " cycloalkenyl group " is meant by concept nature from the unsaturated monocyclic hydrocarbon that comprises two keys removes the substituted univalent perssad (being cyclopentenyl or cyclohexenyl group) that hydrogen atom obtains.
Term " heterocyclic radical " is meant by concept nature from heterocycle alkane removes the substituted univalent perssad that hydrogen atom obtains, and described heterocycle alkane is obtained by using one or two carbon atom of atomic substitutions that is selected from N, O or S by corresponding saturated monocyclic hydrocarbon.The example of heterocyclic radical includes, but not limited to Oxyranyle, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl and morpholinyl.The heterocyclic radical substituent group can be connected on the carbon atom.If substituent group is the nitrogen heterocyclic ring substituent group, then it can be connected on the nitrogen-atoms.
Term " heteroaryl " is meant by concept nature from the aromatic ring that comprises 1,2,3 or 4 heteroatomic monocycle that is selected from N, O or S or dicyclo removes the substituted univalent perssad that hydrogen atom obtains.The example of heteroaryl includes, but not limited to pyrrole radicals, furyl, thienyl, imidazole radicals, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridine radicals, pyrimidine radicals, pyrazinyl, benzimidazolyl, indyl and purine radicals.The heteroaryl substituent group can be connected on the carbon atom or by hetero atom and connect.
Term " three Organosilyls " is meant by low alkyl group or aryl or its and makes up trisubstituted silyl-group that one of them substituent group can be a lower alkoxy.The example of three Organosilyls comprises trimethyl silyl, triethylsilyl, t-butyldimethylsilyl, triisopropyl silicyl, triphenyl silicyl, 3,5-dimethylphenyl silicyl, t-butyldiphenylsilyl, phenyl-tert-butyl group methoxy methyl silylation etc.
In The compounds of this invention, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, heterocyclic radical and heteroaryl can further be substituted by one or more hydrogen atoms are replaced into non-hydrogen group.These groups include, but not limited to halogen, hydroxyl, sulfydryl, amino, carboxyl, cyano group and carbamoyl.
" no matter alkyl " or " aryl " or appear at substituent group (as aryl C
0-8Alkyl) their prefix root of any one in the title, they all should be interpreted as comprising those of qualification implication of " alkyl " and " aryl " that provide above.The amount of carbon atom of indication is (as C
1-10) refer in the alkyl or cycloalkyl part independently or the amount of carbon atom than the moieties of large-substituent that occurs with the prefix root of alkyl wherein.
Term " aryl alkyl " and " alkylaryl " comprise the definition of alkyl wherein as above moieties and wherein aryl define as above aryl moiety.The example of aryl alkyl includes, but not limited to benzyl, luorobenzyl, benzyl chloride base, phenylethyl, phenyl propyl, fluorophenyl ethyl, chlorphenyl ethyl, thienyl methyl, thienyl ethyl and thienyl propyl group.The example of alkylaryl includes, but not limited to tolyl (toluyl), ethylphenyl and propyl group phenyl.
The term " heteroaryl alkyl " that the present invention uses is meant the system that comprises heteroaryl moieties and comprise moieties, and wherein the heteroaryl definition as above.The example of heteroaryl alkyl includes, but not limited to pyridylmethyl, pyridine radicals ethyl and imidazolyl methyl.
Term " halogen " comprises iodine, bromine, chlorine and fluorine.
Term " oxygen (base) " is meant oxygen (O) atom.Term " sulfur (base) " is meant sulfur (S) atom.Term " oxo " is meant=O.Term " oximido " is meant=the N-O group.
Term " replacement " should be thought and comprises by alleged substituent group and replacing repeatedly.When open or claimed a plurality of substituent group part, the chemical compound of replacement can be independently by the replacement of one or more disclosed or claimed substituent group part single or multiple ground.About replacing independently, be meant that (two or more) substituent group can be identical or different.
Under the standard name of using in this specification, the end portion of side chain is described the adjacent functional group towards junction point then shown at first describing.C for example
1-5Alkyl-carbonyl-amino C
1-6Alkyl substituent equals
When selecting The compounds of this invention, this area those of ordinary skill it should be understood that various substituent groups, i.e. R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, V, X, Y, Z, n, m and p selection should meet the known principles of chemical constitution connectedness.
Representative compounds of the present invention demonstrates the affinity of inferior mM usually to α and/or β estrogen receptor.Therefore, The compounds of this invention can be used for treating the mammalian subject with the estrogen function diseases associated.With the chemical compound of pharmacology's effective dose, comprise that the effective salt of its pharmacy is applied to mammal, with treatment and estrogen function diseases associated, as bone loss, hot flush and cardiovascular disease.
The compounds of this invention can use with racemic form or enantiomer monomeric form.For simplicity, some structure is with enantiomer monomeric form diagram, but except as otherwise noted, and they mean and comprise raceme and enantiomeric form.Except as otherwise noted, when The compounds of this invention is represented with cis and trans spatial chemistry, it should be noted that it is relative that spatial chemistry may be interpreted as.
It is normally preferred to use formula (I) chemical compound with the dosage form of enantiomer-pure, because major part or all required biological activitys all are present in the enantiomer monomer.Racemic mixture can be split as the enantiomer monomer by any conventional method.These methods comprise chiral chromatography; The use chiral auxiliary is derived, and separates by chromatograph or recrystallization then; And fractional crystallization diastereoisomeric salt.
The compounds of this invention can be united use with the other medicines of the indication that is used for the treatment of estrogen-mediated.Each component of this class combination medicine can be during treating different time individually dosed, perhaps gradation administration simultaneously or single administering drug combinations.Therefore, the present invention is understood to include the scheme of all these whiles or alternating treatment, and should correspondingly explain term administering or administration ".Should be clear, the combination medicine scope of other medicines of The compounds of this invention and the indication that is used for the treatment of estrogen-mediated comprises and any combination medicine that is used for the treatment of with the pharmaceutical composition of estrogen function diseases associated in principle.
The term " compositions " that the present invention uses should comprise the product of the appointment composition that comprises specified amount and any product that is directly or indirectly obtained by the combination medicine of the appointment composition of specified amount.
The compounds of this invention can be with the peroral dosage form form administration, for example with tablet, capsule (they comprise slow release or time release formulation separately), pill, powder, granule, elixir, tincture, suspension, syrup and emulsion.Equally, they also can pass through intravenous (bolus injection or transfusion), intraperitoneal, part (as eye drop), subcutaneous, intramuscular or transdermal (as patch) form administration, and the form of all uses all is that the those of ordinary skill of pharmaceutical field is known.
Use the dosage of The compounds of this invention to select according to multiple factor, these factors comprise species of patient, race, age, body weight, sex and medical condition; The order of severity of the indication of being treated; Route of administration; Patient's kidney and liver function; And the particular compound or its salt that use.Common specialist, veterinary or clinicist can determine easily and write out a prescription prevention, treatment or suppress the medicine of the effective dose of indication development.
Shown in being used for, do the time spent, oral dose scope of the present invention extremely about 100mg/kg/ days, preferred 0.01-10mg/kg/ days, most preferably 0.1-5.0mg/kg/ days in about 0.01mg/ kg body weight/sky (mg/kg/ days).For oral administration, compositions preferably is tablet form, and tablet comprises 0.01,0.05,0.1,0.5,1.0,2.5,5.0,10.0,15.0,25.0,50.0,100 and 500 milligram of active component, and patient's dosage is treated in adjustment according to symptom.Medicine generally comprises the active component of about 0.01mg to about 500mg, and preferably about 1mg is to the active component of about 100mg.For intravenous route, during continuous transfusion, most preferred dosage range is about 0.1 to about 10mg/kg/ branch.Advantageously, but The compounds of this invention be administered once every day, perhaps every day, accumulated dose can be divided into every day twice, three times or four times.In addition, preferred compound of the present invention can perhaps use transdermal patch form known to a person of ordinary skill in the art by the transdermal route administration by the local intranasal excipient that is fit to that uses with the intranasal form administration.For with transdermal release system form administration, answer successive administration in the whole dosage regimen, but not intermittently administration.
In the method for the invention, the chemical compound that this paper describes in detail can form active component, and they usually with the form of mixtures administration of pharmaceutical diluents, excipient or the carrier (being referred to as " carrier " herein) that are fit to suitably selected at the form of medication of expectation, promptly with conventional pharmaceutical put into practice consistent, often with form administrations such as oral tablet, capsule, elixir, syrup.
For example, oral administration for tablet or capsule form, active medicine component can with oral avirulence pharmaceutical acceptable inert carriers, as mixing such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol; For the oral administration of liquid form, the oral drugs composition can with any oral avirulence pharmaceutical acceptable inert carriers, as mixing such as ethanol, glycerol, water.Moreover, when expecting or needing, binding agent, lubricant, disintegrating agent and the coloring agent that is fit to can be mixed in the mixture.The binding agent that is fit to comprises starch, gelatin, natural saccharide (as glucose and beta lactose), corn sweetener, natural and synthetic natural gum (as arabic gum, tragacanth or sodium alginate), carboxymethyl cellulose, Polyethylene Glycol, wax etc.The lubricant that uses in these dosage forms comprises enuatrol, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride etc.Disintegrating agent includes, but not limited to starch, methylcellulose, agar, bentonite, xanthan gum etc.
The compounds of this invention also can be with the liposome drug delivery system, for example little monolayer capsule, big monolayer capsule and the administration of multilamellar scrotiform formula.Liposome can be formed as cholesterol, stearmide or phosphatidylcholine by various phospholipid.
The compounds of this invention also can discharge as the link coupled with it independent carrier of compound molecule by using monoclonal antibody.The compounds of this invention can also with the soluble polymer coupling as target medicine carrier.This base polymer can comprise polyvinylpyrrolidone, pyran co-polymer, poly-hydroxypropyl Methacrylamide-phenol, poly-hydroxyl-ethyl asparagine-phenol or the poly(ethylene oxide)-polylysine that is replaced by the palmityl residue.In addition, The compounds of this invention can be used to obtain the biodegradable polymers coupling of controlled release drug with a class, and described polymer is copolymer, poly epsilon caprolactone lactone, poly butyric, poe, polyacetals, poly-dihydropyran, polybutylcyanoacrylate and crosslinked or the amphoteric hydrogel block copolymer of for example polylactic acid, polyglycolic acid, polylactic acid and polyglycolic acid.
Noval chemical compound of the present invention can use the raw material that is fit to be prepared according to the method for following reaction scheme and embodiment, uses following specific embodiment further to illustrate.But the chemical compound of embodiment illustrated should not be construed as and forms unique kind that the present invention considers.The following example further illustrates the detailed preparation method of The compounds of this invention.This area professional and technical personnel can use the following preparation steps of the condition that changed and method to prepare these chemical compounds with fully aware of.Unless indication is arranged in addition, all temperature all are degree centigrade.
Prepare The compounds of this invention according to following general reaction scheme I:
Reaction scheme I. cis-dihydrobenzo oxathiin
(DIHYDROBENZOXATHIINE) and the universal synthesis method of benzodioxane
For this scheme, with the suitable functionalized two-phenol II (X=O that obtains easily, Y=O) or according to the sulfydryl-phenol II (X=O of literature method preparation, Y=S) with bromo-ketone derivatives III (being easy to by corresponding ketone) reaction by making with phenyl trimethyl tribromide ammonium (PTAB) bromination, this is reflected at tertiary amine base, as triethylamine, under the existence of diisopropyl ethyl amine etc., at solvent, as dimethyl formamide (DMF), Methanamide, acetonitrile, dimethyl sulfoxine (DMSO), oxolane (THF), in the dichloromethane etc., under-20-80 ℃ temperature, carry out obtaining substitution product IV until reacting completely.When X=Y=O, R
3Can only be-OR
6Perhaps, as X=Y=O and R
2Be-OR
6The time, obtain essential cyclisation intermediate by transposition ketone and bromo functional groups.When some substituent group that exists will change phenol oxygen atom reactive,, need these regulations for preparing these chemical compounds of the present invention.
With the intermediate compound IV reductive ring closure, this is reflected at organic acid, as trifluoroacetic acid, trifluoromethanesulfonic acid etc., perhaps lewis acid is as boron trifluoride diethyl etherate thing, stannum dichloride etc. and Reducing agent, as trisubstituted silane, under the existence as triethyl-silicane etc., at solvent, as under-40-100 ℃ temperature, carrying out under the existence of dichloromethane, chloroform, THF, toluene etc. until reacting completely, obtain the product V of cyclization, aryl substituent in the wherein newly-generated ring and R
5Spatial chemistry only be cis.Having similarly, the formation of trans stereochemical intermediate is depicted in the following general scheme II.
Work as R
6When being protecting group, remove this protecting group among the product V in the mode that meets its character.These methods have abundant report in introducing the document of standard textbook, Greene for example, T.W. and Wuts, P.G.M., Protective Groups in Organic Synthesis, ThirdEd., Wiley, New York (1999).In addition, should be clear, can have any amount of substituent R
1-R
4Be-OR
6Perhaps comprise-OR
6, perhaps R
5Can comprise-OR
6, R wherein
6It is protecting group; And should be clear, protecting group is chemically different in these cases, promptly when needs, they optionally are removed.For example, in product V, R
6Be methoxy (MOM), R
2Be-OR
6, R wherein
6Be benzyl (Bn), R
5By R
7The phenyl that replaces, wherein R
7Be OR
6, R wherein
6Be triisopropyl silicyl (TIPS), and all substituent groups of not indicating all are hydrogen.As shown, as the part of synthetic order, remove the MOM group with need having precedence over TIPS or Bz group selectivity.The method of using Green and Wuts to describe can generate preferred intermediate V, wherein R
6Be H, R
2Be-OBn R
5Be that right-OTIPS-phenyl and substituent group that all are not indicated all are hydrogen.Should also be noted that in product V, work as R
2Or R
3In one be OR
6The time, R
6Must be protecting group, and before removing it, existence-OR
6Group must be sheltered with different protecting groups.
Then with alcohol intermediate VI and reagent HO (CH
2)
nNZ
2With Mitsunobu reactive mode reaction, wherein with them and trisubstituted phosphine, as triphenylphosphine and diazonium dicarboxylic ester, the solvent that is being fit to as azodicarboxylate's diisopropyl ester, in THF, mix until reacting completely down at 0 ℃-80 ℃, obtain link coupled product I.For the existing sufficient document record of the changing factor of Mitsunobu reaction, be incorporated herein these documents as a reference: Mitsunobu, O.Synthesis, 1981,1; Castro, B.R.Org.React.1983,29,1; Hughes, D.L.Org.React.1992,42,335.
At last, should be clear, after the Mitsunobu reaction, if any R group is-OR in I
6Perhaps comprise-OR
6, R wherein
6Be protecting group, the proper method that then utilizes Green and Wuts to describe is removed them, to obtain R
6Be that H is an end product.
Scheme II. trans-dihydrobenzo oxathiin and
The universal synthesis method of benzodioxane
The reaction scheme of universal method for preparing the transisomer of I for top being used to, in the mixed solvent or THF equal solvent of methanol and dichloromethane, at 0 ℃ to room temperature, the ketone intermediate compound IV reduction number that reaction scheme I is obtained with sodium borohydride, super hydride (super hydride) etc. obtains similar hydroxy intermediate VII minute to a few hours.
At acidic catalyst, under the existence as amberlyst 15 or trifluoromethanesulfonic acid etc., in solvent such as toluene or dichloromethane etc., to reflux temperature, realize the cyclization of intermediate VII in room temperature, obtain trans-compound VIII as main isomer.
Among remaining the synthetic order for preparing trans I and the reaction scheme I generalized and describe in detail above identical.
The reaction scheme of following mask body is summarized, and prepares wherein X=O and Y=SO or SO
2The compounds of this invention.
The universal synthesis method of scheme II I. dihydrobenzo oxathiin dioxide
For scheme II I, in solvent as dichloromethane etc., at 0 ℃ to reflux temperature, with Compound I of the present invention oxidant, as metachloroperbenzoic acid or cross trifluoroacetic acid and carry out peroxidating, preparation trioxide intermediate X.Next, in two-phase medium, for example in the medium of ethyl acetate and water etc., use Reducing agent,, X is carried out the selectivity deoxygenated on nitrogen-atoms, obtain I as processing such as sodium acid sulfites.
In chemical compound of the present invention, X is O and Y S preferably preferably.
In chemical compound of the present invention, R
1, R
2, R
3And R
4Be preferably selected from hydrogen, C
1-5Alkyl, C
3-8Cycloalkyl, C
1-5Alkenyl, C
1-5Alkynyl ,-OR
6And halogen.
In chemical compound of the present invention, R
5Be preferably selected from C
3-8The phenyl of cycloalkyl, phenyl and replacement.
In chemical compound of the present invention, R
6Be preferably selected from hydrogen, C
1-5Alkyl, benzyl, methoxy and triisopropyl silicyl.
In chemical compound of the present invention, preferred group is those chemical compounds, wherein R
1And R
4Be hydrogen, R
2And R
3Be independently-OH and R
5Be independently selected from the phenyl of phenyl and replacement.
In chemical compound of the present invention, preferably another little compounds is those chemical compounds, wherein R
1Be independently selected from fluorine and chlorine, R
4Be hydrogen, R
2And R
3Be independently-OH and R
5Be independently selected from the phenyl of phenyl and replacement.
In chemical compound of the present invention, most preferred one little compounds is those chemical compounds, wherein R
1And R
4Be hydrogen, R
2Be-OH and R
5Be independently selected from phenyl and to hydroxyl-phenyl.
The universal synthesis method of reaction scheme IV. dihydrobenzo oxathiin oxide
For reaction scheme IV, in the solvent of for example dichloromethane, ether, acetone etc., at-78 ℃ to room temperature, use monovalent or excessive a little oxidant, handle several minutes carefully to a few hours as metachloroperbenzoic acid or dimethyl dioxirane (dimethyldioxirane) etc., make the intermediate V of scheme reaction I that single oxidation take place, obtain corresponding sulfoxide intermediate X I.Among the synthetic order of all the other of preparation I and the reaction scheme I generalized and describe in detail above identical.
In chemical compound of the present invention, X is O and Y S preferably preferably.
In chemical compound of the present invention, R
1, R
2, R
3And R
4Be preferably selected from hydrogen, C
1-5Alkyl, C
3-8Cycloalkyl, C
1-5Alkenyl, C
1-5Alkynyl ,-OR
6And halogen.
In chemical compound of the present invention, R
5Be preferably selected from C
3-8The phenyl of cycloalkyl, phenyl and replacement.
In chemical compound of the present invention, R
6Be preferably selected from hydrogen, C
1-5Alkyl, benzyl, methoxy and triisopropyl silicyl.
In chemical compound of the present invention, preferred group is those chemical compounds, wherein R
1And R
4Be hydrogen, R
2And R
3Be independently-OH and R
5Be independently selected from the phenyl of phenyl and replacement.
In chemical compound of the present invention, preferably another little compounds is those chemical compounds, wherein R
1Be independently selected from fluorine and chlorine, R
4Be hydrogen, R
2And R
3Be independently-OH and R
5Be independently selected from the phenyl of phenyl and replacement.
In chemical compound of the present invention, most preferred one little compounds is those chemical compounds, wherein R
1And R
4Be hydrogen, R
2Be-OH and R
5Be independently selected from phenyl, a hydroxy phenyl and p-hydroxybenzene.
Embodiment 1
The routine preparation of phenylmercaptan.
The Wermer that describes in the scheme above adopting, G.; Biebrich, the United States Patent (USP) 2,276,553 and 2,332 of W., 418 known method slightly makes improvements, and prepares functionalized phenylmercaptan..
Method according to following document: Maxwell, S.J.Am.Chem.Soc.1947,69,712; Hanzlik, people such as R.P., J.Org.Chem.1990,55,2736.
Embodiment 2
The preparation of 2-thiophene-4-methoxyl group-benzophenone
Under 0 ℃, blanket of nitrogen, (1.49g 13.8mmol) adds AlCl in the solution in anhydrous methylene chloride (5mL) toward the methoxybenzene that stirs
3(1.2320g, 9.2mmol), drip then the 2-thiophen acetyl chloride (0.57mL, 4.6mmol).To react and stir 1.5 hours, impouring contains in the separatory funnel of ice/saline/EtOAc then.Organic layer is further used the salt water washing, through dried over sodium sulfate and vacuum concentration.The gained residue uses the 30%EtOAc/ hexane as eluant, through the silica gel chromatography purification, obtains the expection product of yellow oily.
1H NMR 500MHz (CDCl
3) ppm (δ): 3.89 (s, 3H), 4.46 (s, 2H), 6.98 (m, 4H), 7.24 (d, 1H) and 8.05 (d, 2H).
Embodiment 3
The preparation of 2-thiophene-4-hydroxyl-benzophenone
Under blanket of nitrogen, with 2-thiophene-4-methoxyl group-benzophenone of generating among the embodiment 2 (0.8294g, 3.5mmol) and pyridine-HCl (4.0627g, mixture 35.2mmol) heated 6 hours at 190 ℃.By aliquot monitoring reaction through the post processing of TLC (30%EtOAc/ hexane) detecting reactant.Reactant is cooled off in ice bath and add ice/water.The gained mixture extracts with EtOAc.Organic extract liquid is with 2N HCl and salt water washing, through dried over sodium sulfate and vacuum concentration.The brown residue use of gained 30%EtOAc/ hexane through the silica gel chromatography purification, obtains the solid expection product of yellow/orange as eluant.
1H NMR 500MHz (CDCl
3) ppm (δ): 4.43 (s, 2H), 5.60 (bs, 1H), 6.90 (d, 2H), 6.92 (m, 1H), 6.97 (m, 1H), 7.22 (d, 1H) and 8.00 (d, 2H).
Embodiment 4
The routine preparation of cycloalkyl-4-hydroxyl-benzophenone
Under 0 ℃, in 2-cycloalkyl-1-(4-methoxyl group-phenyl)-ethyl ketone that stirs [according to people's such as Barrio, J.Med.Chem., 1971,14,898 method preparation] anhydrous methylene chloride solution, add 3.6 normal aluminum chloride and 3.0 normal isopropyl mercaptans.Remove ice-water bath and under inert nitrogen atmosphere, the reactant mixture restir is spent the night.With in the mixture of reactant mixture impouring 2N HCl/ ice and use ethyl acetate extraction.Acetic acid ethyl acetate extract salt water washing through anhydrous sodium sulfate drying, is filtered and evaporation.Through the silica gel chromatography purification, obtain corresponding 2-cycloalkyl-1-(4-hydroxyl-phenyl)-ethyl ketone.
Use the previous experiments method to prepare following compounds: 2-cyclohexyl-1-(4-hydroxyl-phenyl)-ethyl ketone: 70% productive rate, use dichloromethane-ethyl acetate (50: 1) as chromatographic eluents.
1H NMR 500MHz (CDCl
3) ppm (δ): 1-2.0 (and m, 11H), 2.96 (d, 1H), 5.6 (bs, 1H), 6.92 (d, 2H) and 7.95 (d, 2H).2-cyclopenta-1-(4-hydroxyl-phenyl)-ethyl ketone: 74% productive rate, use dichloromethane-ethyl acetate (50: 1) as chromatographic eluents.
1H NMR 500MHz (CDCl
3) ppm (δ): 1.2-1.92 (and m, 10H), 2.4 (m, 1H), 2.96 (d, 1H), 5.6 (bs, 1H), 6.91 (d, 2H) and 7.95 (d, 2H).
Embodiment 5
The preparation of isopropyl-4-hydroxyl-benzophenone
Under blanket of nitrogen, toward isovaleric acid (1.4mL, 13.0mmol) and phenol (1.0253g adds BF in mixture 10.9mmol)
3OEt
2(15mL).The gained mixture was about 3.5 hours of 80 ℃ of heating.Extract with reactant impouring ice/2N HCl and with EtOAc.Organic extract liquid salt water washing through dried over sodium sulfate and vacuum concentration, obtains yellow residue.After using the 30%EtOAc/ hexane to carry out silica gel chromatography, isolate the end-product of light yellow oil as eluant.Through placing in room temperature, this oil solidifies, and obtains white solid.
1H?NMR?500MHz(CDCl
3)ppm(δ)：1.01(d，6H)，2.27(m，1H)，2.81(d，2H)，6.99(d，2H)，7.93(d，2H)。
Embodiment 6
The preparation of 4-pyridine radicals-4-hydroxyl-benzophenone
In the dry flask of stirring rod is installed, add the 2.5M n-BuLi hexane solution (18mL, 45.0mmol) and under blanket of nitrogen, be cooled to 0 ℃.Slowly add diisopropylamine (6.4mL, 45.7mmol) solution in distillatory THF (20mL).Stir after 25 minutes, (2.0mL, 21.4mmol) solution in distillatory THF (8mL) is added in this reactant with the 4-picoline.The gained red solution was stirred 25 minutes, remove ice bath then.Through 30 minutes, add cyanophenol (2.5670g, 21.4mmol) solution in distillatory THF (20mL) by Dropping funnel.By adding phenol, this reactant becomes heavy-gravity slurry, wherein separates out red/brown tar.Further add the difficulty that THF is not alleviated stirring.Make reactant room temperature placement 16 hours and with its impouring ice/saturated NH
4In the mixed liquor of Cl/EtOAc.The intermediate enamine is precipitated out from this mixture with insoluble yellow solid form, and collects through vacuum filtration.This solid is dissolved among the 2N HCl again.Collection also extracts with 2N HCl/ ice from the ethyl acetate layer that filtrate obtains.The 2N HCl solution of acid extract aqueous solution and enamine merged and stirring at room 16 hours.This acid solution washs with EtOAc, is cooled to 0 ℃ and be neutralized to pH7 with saturated sodium bicarbonate.The expection product is precipitated out from solution and collects with the yellow solid form, with cold water washing and vacuum drying.
1H NMR 500MHz (d-acetone) ppm (δ): 4.37 (s, 2H), 6.97 (d, 2H), 7.31 (d, 2H), 8.01 (d, 2H), 8.52 (bs, 2H).
Embodiment 7
The preparation of 3-pyridine radicals-4-hydroxyl-benzophenone
According to the method for general introduction among the embodiment 6, different is is added to the THF solution of 1 equivalent HMPA in the reactant, adds diisopropylamine then, prepares 3-pyridine radicals-4-hydroxyl-benzophenone by the 3-picoline.Post processing is slightly different, promptly uses the hydrolysis of 2N HCl optional.As an alternative, reactant can be assigned to ice/saturated NH simply
4Among Cl and the EtOAc.Organic layer salt water washing is through dried over sodium sulfate and vacuum concentration.Residue CH
2Cl
2With the EtOAc development, obtain the expection product of orange solids.
1H NMR 500MHz (d-acetone) ppm (δ): 4.39 (s, 2H), 6.97 (d, 2H), 7.31 (m, 1H), 7.68 (m, 1H), 8.01 (d, 2H), 8.43 (m, 1H), 8.52 (m, 1H).
Embodiment 8
The routine preparation of cycloalkyl-4-triisopropyl siloxy-benzophenone
Under 0 ℃, add 1.3 equivalent diisopropyl ethyl amines and 1.2 equivalent triisopropyl chloromethane silane (TIPSCl) in 2-cycloalkyl-1-(4-hydroxyl-phenyl)-solution of ethyl ketone in dry DMF that makes in the embodiment 4 that stirs.Remove ice-water bath and under inert nitrogen atmosphere, stir this reactant mixture and show react completely (1-3 hour) until TLC.Be assigned to reactant mixture in the ether/2N HCl/ ice and separate organic facies, wash twice with water, use the salt water washing,, filter also and evaporate through anhydrous sodium sulfate drying.Through the silica gel chromatography purification, obtain corresponding 2-cycloalkyl-1-(4-three isopropoxies-phenyl)-ethyl ketone.
Use the previous experiments method to prepare following compounds: 2-cyclohexyl-1-(4-triisopropyl siloxy-phenyl)-ethyl ketone; Use dichloromethane-hexane (1: 1) as chromatographic eluents.
1H NMR 500MHz (CDCl
3) ppm (δ): 1.13 (d, 18H), 1-1.99 (m, 14H), 2.78 (d, 1H), 6.91 (d, 2H) and 7.89 (d, 2H).2-cyclopenta-1-(4-triisopropyl siloxy-phenyl)-ethyl ketone: use dichloromethane-hexane (1: 1) as chromatographic eluents.
1H NMR 500MHz (CDCl
3) ppm (δ): 1.12 (d, 18H), 1.2-1.91 (m, 13H), 2.4 (m, 1H), 2.95 (d, 1H), 6.92 (d, 2H) and 7.9 (d, 2H).
Embodiment 9
The routine preparation of alkyl-4-triisopropyl siloxy-benzophenone
Under 0 ℃, blanket of nitrogen, add the mixture of 1.3 normal 60%NaH in mineral oil in 2-alkyl-1-(4-hydroxyl-phenyl)-solution of ethyl ketone in distillatory THF that makes in embodiment 3,6 and 7.After not having gas to emit, drip 1.1 equivalents again and with gained solution stirring 30 minutes.With reactant distribution in ice/water and EtOAc.Organic layer salt water washing is through dried over sodium sulfate and vacuum concentration.Obtain corresponding 2-alkyl-1-(4-triisopropyl siloxy-phenyl)-ethyl ketone through the silica gel chromatography purification.
Use the previous experiments method to prepare following compounds: 2-(2-thiophene)-1-(4-triisopropyl siloxy-phenyl)-ethyl ketone: to use the 15%EtOAc/ hexane as chromatographic eluents, isolate orange/yellow solid.
1H NMR 500MHz (CDCl
3) ppm (δ) 1.14 (and d, 18H), 1.30 (m, 3H), 4.42 (s, 2H) and 6.93-7.98 (m, 7H).2-(4-pyridine radicals)-1-(4-triisopropyl siloxy-phenyl)-ethyl ketone: use the 40%EtOAc/ hexane as chromatographic eluents, isolate yellow solid.
1H NMR 500MHz (CDCl
3) ppm (δ): 1.14 (d, 18H), 1,30 (m, 3H), 4.28 (s, 2H), 6.97 (d, 2H), 7.35 (m, 1H), 7.69 (m, lH), 7.97 (d, 2H) and 8.56 (bs, 2H).2-(3-pyridine radicals)-1-(4-triisopropyl siloxy-phenyl)-ethyl ketone: use the 40%EtOAc/ hexane as chromatographic eluents, isolate yellow solid.
1H NMR 500MHz (CDCl
3) ppm (δ): 1.14 (d, 18H), 1.20 (m, 3H), 4.18 (s, 2H), 6.82 (d, 2H), 7.10 (d, 2H), 7.82 (d, 2H) and 8.43 (d, 2H).
Embodiment 10
Alkyl-and the conventional bromination process of cycloalkyl-4-triisopropyl siloxy-benzophenone
Under 0 ℃, the 2-alkyl that makes toward the embodiment 8 and 9 that stirs-and 2-cycloalkyl-1-(4-triisopropyl siloxy-phenyl)-solution of ethyl ketone in anhydrous THF in add the full bromide of 1.0 equivalent trimethyl ammonium phenyl.Remove ice-water bath and under inert nitrogen atmosphere with reaction-ure mixture restir 1 hour.Reaction-ure mixture is assigned in ethyl acetate/saline/ice/5% sodium thiosulfate/sodium bicarbonate, separates organic facies, use the salt water washing,, filter and evaporation through anhydrous sodium sulfate drying.Obtain corresponding 2-cycloalkyl-2-bromo-1-(4-triisopropyl siloxy-phenyl)-ethyl ketone through the silica gel chromatography purification.
Use the previous experiments method to prepare following compounds: 2-cyclohexyl-2-bromo-1-(4-triisopropyl siloxy-phenyl)-ethyl ketone: to use dichloromethane-hexane (1: 1) as chromatographic eluents.
1H NMR 500MHz (CDCl
3) ppm (δ): 1.14 (d, 18H), 0.98-2.27 (m, 15H), 4.91 (d, 1H), 6.94 (d, 2H) and 7.94 (d, 2H).2-cyclopenta-2-bromo-1-(4-triisopropyl siloxy-phenyl)-ethyl ketone: use dichloromethane-hexane (1: 1) as chromatographic eluents.
1H NMR 500MHz (CDCl
3) ppm (δ): 1.13 (d, 18H), 1.1-2.2 (m, 11H), 2.8 (m, 1H), 4.98 (d, 1H), 6.94 (d, 2H) and 7.96 (d, 2H).2-(2-thiophene)-2-bromo-1-(4-triisopropyl siloxy-phenyl)-ethyl ketone: stirred 40 minutes down at 0 ℃; Isolate burgundy oil, this product need not purification and promptly can be used for the next step.
1H NMR500MHz (CDCl
3) ppm (δ): 1.13 (d, 18H), 1.30 (m, 3H), 6.73 (s, 1H), 6.97 (d, 2H), 7.00 (m, 1H), 7.30 (m, 1H), 7.49 (d, 1H) and 8.00 (d, 2H).2-(4-pyridine radicals)-2-bromo-1-(4-triisopropyl siloxy-phenyl)-ethyl ketone: add the 2 full bromides of normal trimethyl ammonium phenyl and stirred 1 hour at 0 ℃; Isolate orange/yellow oil, this product need not purification and promptly can be used for the next step.
1H NMR 500MHz (CDCl
3) ppm (δ): 1.03 (d, 18H), 1.21 (m, 3H), 6.21 (s, 1H), 6.98 (d, 2H), 7.40 (d, 2H), 7.90 (d, 2H) and 8.57 (d, 2H).2-(3-pyridine radicals)-2-bromo-1-(4-triisopropyl siloxy-phenyl)-ethyl ketone: add the 2 full bromides of normal trimethyl ammonium phenyl and stirred 3 hours at 0 ℃; Isolate orange/yellow oil, this product need not purification and promptly can be used for the next step.
1H NMR 500MHz (CDCl
3) ppm (δ): 1.13 (d, 18H), 1.30 (m, 3H), 6.30 (s, 1H), 6.98 (d, 2H) and 7.39-8.75 (m, 6H).
Embodiment 11
The preparation of 2-isopropyl-2-bromo-1-(4-hydroxy phenyl)-ethyl ketone
According to the method for general introduction among the embodiment 10, and use the product that is obtained by embodiment 5, isolate 2-isopropyl-2-bromo-1-(4-the hydroxy phenyl)-ethyl ketone of yellow oily, this product need not purification and promptly can be used for the next step.
1H NMR 500MHz (CDCl
3) ppm (δ): 1.01 (d, 3H), 1.21 (d, 3H), 2.46 (m, 1H), 4.93 (d, 1H), 6.96 (d, 2H) and 7.96 (d, 2H).
Embodiment 12
The routine preparation of bromo ketone
Steps A
Under 0 ℃, in the solution of the anhydrous deoxybezoin, desoxybenzoin of 3.0g (13.2 mM) (fresh azeotropic) in 25mL DMF that stirs, add the pure diisopropyl ethyl amine of 5.7mL (5.7 mM) with toluene.In the solution of this stirring, add 1.25mL (19.73 mM) chloromethyl methyl ether (MOMCl) lentamente.Remove ice-water bath and with this mixture restir 18 hours under blanket of nitrogen.Then with in this mixture impouring saturated sodium bicarbonate solution, with the EtOAc extraction, extract washes with water and through anhydrous magnesium sulfate drying.Behind the evaporating solvent, residue obtains solid product through silica gel chromatography purification (EtOAc/ hexane=1: 1).
1H?NMR(400?MHz，CDCl
3)δ(ppm)：8.0(d，2H)，7.19(d，2H)，7.10(d，2H)，6.8(d，2H)，5.23(s，2H)，4.8(s，1H)，4.2(s，2H)，3.5(s，3H)。
Step B
Under 0 ℃, product (423mg toward the steps A acquisition of stirring, 1.55 add triisopropyl silyl chloride (3.1 mM) mM) and in the solution of imidazoles (211mg, 3.1 mMs) in the 20mL dry DMF, and make this reactant mixture be warming to room temperature and restir 2-3 hour.Reactant adds sodium bicarbonate aqueous solution to be handled and extracts with EtOAc.Organic layer is with the salt water washing and use MgSO
4Dry.Through chromatograph (10%EtOAc/ hexane), obtain expecting product.
1H?NMR(400MHz，CDCl
3)δ(ppm)：8.0(d，2H)，7.12(d，2H)，7.08(d，2H)，6.82(d，2H)，5.21(s，2H)，4.18(s，2H)，3.5(s，3H)，1.24(m，3H)，1.1(d，18H)。
Step C
Under 0 ℃, the chemical compound (0.5g, 1.16 mMs) that obtains toward step B adds the 0.39g full bromide of (1.16 mM) trimethylphenyl ammonium (PTAB) in the mixture of the anhydrous THF of 100mL.Remove ice-water bath and with this mixture restir 1 hour.Then this solution is filtered and water and salt water washing, through MgSO
4Dry.Remove and desolvate, obtain the mixture (the MOM group is partly removed) of bromo ketone, because they are for stratographic unstability, this product need not to be further purified and can use.The bromo ketone that has the MOM group:
1H NMR (400MHz, CDCl
3) δ (ppm): 8.0 (d, 2H), 7.4 (d, 2H), 6.88 (d, 2H), 6.86 (d, 2H), 6.36 (s, 1H), 1.24 (m, 3H), 1.1 (d, 18H); The bromo ketone that does not have the MOM group:
1H NMR (400MHz, CDCl
3) δ (ppm): 7.94 (d, 2H), 7.4 (d, 2H), 6.88 (d, 2H), 6.86 (d, 2H), 6.36 (s, 1H), 1.24 (m, 3H), 1.1 (d, 18H).
Embodiment 13
The preparation of following formula: compound
Use the method for embodiment 12 (step C) to prepare required bromo ketone.
1H?NMR(400MHz，CDCl
3)δ(ppm)7.94(d，2H)，7.56(m，2H)，7.38(m，3H)，6.9(d，2H)，6.36(s，2H)，1.28(m，3H)，1.1(d，18H)。
Embodiment 14
The preparation of following formula: compound
Use the method for embodiment 12 (step C) to prepare required bromo ketone.
1H?NMR(400MHz，CDCl
3)δ(ppm)7.9(d，2H)，7.5(d，2H)，6.9(d?&?d，4H)，6.4(s，1H)，3.8(s，3H)，1.28(m，3H)，1.1(d，18H)。
Embodiment 15
The preparation of following formula: compound
Steps A
At room temperature, an oxybenzene compound and diisopropyl ethyl amine (0.13mL that past 0.1g (0.37 Bo mole) embodiment 12 steps A that stir obtain, (0.05mL 2eq) and under blanket of nitrogen heats this mixture 3 hours down at 85 ℃ 2eq) to add pure MOMCl in the solution in 5mL DMF lentamente.Then with in this mixture impouring saturated sodium bicarbonate solution,, wash with water and through dried over mgso with the EtOAc extraction.Behind the evaporating solvent, residue obtains the MOM product of purified solid two protections through silica gel chromatography purification (EtOAc/ hexane=1: 1).
1H NMR (400MHz, CDCl
3) δ (ppm): 8.0 (d, 2H), 7.19 (d, 2H), 7.10 (d, 2H), 7.02 (d, 2H), 5.23 (s, 2H), 5.2 (s, 2H), 4.2 (s, 2H), 3.5 (two s, 6H).
Step B
The product of steps A is handled with bromine, obtained bromo ketone.
1H NMR (400MHz, CDCl
3) δ (ppm): 8.0 (d, 2H), 7.45 (d, 2H), 7.10 (two d, 4H), 6.4 (s, 1H), 5.23 (two s, 4H), 3.5 (two s, 6H).
Embodiment 16
The routine preparation of following formula: compound
Under 0 ℃, toward the 2-phenylmercaptan. (0.2g, 1.6 mMs) and the Et of the prepared fresh that stirs
3(0.34mL 2eq) adds the solution of 0.627g (1.232 mM) bromo ketone (the step C by embodiment 12 makes) in 13mL DMF to N lentamente in the solution in 15mL DMF.This reactant mixture stirring at room 3 hours, is assigned in saturated sodium bicarbonate and the ethyl acetate then, separates each layer, water layer reuse ethyl acetate extraction.The organic layer that merges filters and vacuum evaporation through dried over sodium sulfate.The grease that obtains obtains oily expection product through flash chromatography (EtOAc/Hex=1/4) purification.
1H NMR (400MHz, acetone-d
6) δ (ppm): 8.0 (d, 2H), 7.2-6.6 (m, 8H), 6.8 (d, 2H), 6.2 (s, 1H), 5.24 (s, 2H), 3.4 (s, 3H), 1.22 (m, 3H), 1.1 (d, 18H); MSm/z 575 (M
++ 23).
Embodiment 17
The cyclization of coupled product
According to the method for general introduction among the embodiment 16, with 1, the bromide that 2-dihydroxy benzenes and embodiment 15 obtain is converted into product, uses EtOAc/ hexane (1/4) as eluant, through this product of silica gel chromatography purification.MS?m/z?448(M
++23)。
Embodiment 18
The preparation of following compounds
According to the method for general introduction among the embodiment 16, and 0.83g (3.6 mM) 4-benzyloxy-phenylmercaptan. that uses embodiment 1 to make, use EtOAc/ hexane (1/5) as eluant, behind the silica gel chromatography purification, obtain product A and product B.A:
1H NMR (400MHz, acetone-d
6) δ (ppm): 8.15 (s, 1H), 7.8 (d, 2H), 7.4 (m, 5H), 6.98 (d, 2H), 6.98 (d, 1H), 6.75 (d ﹠amp; D, 4H), 6.0 (s, 1H), 5.62 (s, 1H), 5.0 (s, 2H), 1.22 (m, 3H), 1.15 (d, 18H).B:
1H NMR (400MHz, acetone-d
6) δ (ppm): 8.0 (d, 2H), 7.5 (m, 5H), 7.18 (d, 2H), 7.04 (d, 2H), 6.96 (d, 1H), 6,8 (d, 2H), 6.56 (d, 1H), 6.32 (dd, 1H), 6.1 (s, 1H), 5.25 (s, 2H), 5.09 (s, 1H), 3,4 (s, 3H), 1.22 (m, 3H), 1.1 (d, 18H).
Embodiment 19
The preparation of following formula: compound
According to the method for general introduction among the embodiment 16, and the bromo ketone that uses (2.3 mM) embodiment 14 l.1g to obtain, use EtOAc/ hexane (1/5) as eluant, behind silica gel chromatography, obtain the expection product.
1H NMR (400MHz, acetone-d
6) δ (ppm): 8.46 (br s, 1H), 7.98 (d, 2H), 7.48-7.3 (m, 5H), 7.24 (d, 2H), 7.4 (d, 1H), 6.92 (d, 2H), 6.82 (d, 2H), 6.56 (d, 1H), 6.38 (dd, 1H), 6.1 (s, 1H), 5.04 (s, 2H), 3.72 (s, 3H), 1.25 (m, 3H), 1.1 (d, 18H).
Embodiment 20
The preparation of following formula: compound
According to the method for general introduction among the embodiment 16, the bromo ketone that uses 0.74g (1.5 mM) embodiment 12 (step C) to obtain uses EtOAc/ hexane (1/5) as eluant, behind silica gel chromatography, obtains the expection product.
1H NMR (400MHz, acetone-d
6) δ (ppm): 7.92 (d, 2H), 7.46-7.1 (m, 5H), 7.18 (d, 2H), 6.84 (d, 2H), 6.78 (d, 2H), 6.42 (d, 1H), 6.36 (d, 1H), 5.98 (s, 1H), 5.02 (s, 2H), 2.2 (s, 3H), 1.22 (m, 3H), 1.1 (d, 18H).
Embodiment 21
The preparation of following formula: compound
Method according to general introduction among the embodiment 16, and the phenylmercaptan. derivant of using bromo ketone that 0.8g (1.57 mM) embodiment 12 (step C) obtains and embodiment 1 to make, use EtOAc/ hexane (1/5) as eluant, behind silica gel chromatography, obtain the expection product.
1H NMR (400MHz, acetone-d
6) δ (ppm): 7.9 (d, 2H), 7.5-7.3 (m, 5H), 7.12 (d, 2H), 6.9 (d, 1H), 6.84 (d, 2H), 6.79 (d, 2H), 6.4 (d, 1H), 6.0 (s, 1H), 5.1 (s, 2H), 2.1 (s, 3H), 1.25 (m, 3H), 1.1 (d, 18H).
Embodiment 22
The preparation of following formula: compound
Method according to general introduction among the embodiment 16, and the phenylmercaptan. derivant of using bromo ketone that 0.56g (1.1 mM) embodiment 12 (step C) obtains and 0.19g (0.73 mM) embodiment 1 to prepare, use EtOAc/ hexane (1/5) as eluant, behind silica gel chromatography, obtain the expection product.
1H NMR (400MHz, acetone-d
6) δ (ppm): 7.9 (d, 2H), 7.48-7.3 (m, 5H), 7.16 (d, 2H), 6.84 (d, 2H), 6.78 (d, 2H), 6.42 (d, 1H), 6.38 (d, 1H), 5.96 (s, 1H), 5.1 (s, 2H), 2.6 (q, 2H), 1.22 (m, 3H), 1.1 (d, 18H), 1.1 (t, 3H).
Embodiment 23
The preparation of following formula: compound
Method according to general introduction among the embodiment 16, and the phenylmercaptan. derivant of using bromo ketone that 2.04g (4.33 mM) embodiment 12 (step C) obtains and embodiment 1 to make, use EtOAc/ hexane (1/5) as eluant, behind silica gel chromatography, obtain the expection product.
1H NMR (400MHz, acetone-d
6) δ (ppm): 7.9 (d, 2H), 7.5-7.3 (m, 5H), 7.12 (d, 2H), 6.92 (d, 1H), 6.84 (d, 2H), 6.78 (d, 2H), 6.42 (d, 1H), 6.0 (s, 1H), 5.1 (s, 2H), 2.7 (q, 2H), 1.24 (m, 3H), 1.1 (d ﹠amp; T, 21H).
Embodiment 24
The preparation of following formula: compound
Method according to general introduction among the embodiment 16, and the phenylmercaptan. derivant of using bromo ketone that 2.0g (4.33 mM) embodiment 12 (step C) obtains and embodiment 1 to make, use EtOAc/ hexane (1/5) as eluant, behind silica gel chromatography, obtain the expection product.
1H NMR (400MHz, acetone-d
6) δ (ppm): 7.8 (d, 2H), 7.62 (d, 2H), 7.48-7.3 (m, 8H), 7.12 (d, 2H), 6.8 (d, 2H), 6.76 (2H, d), 6.28 (d, 1H), 6.18 (d, 1H), 6.0 (s, 1H), 5.24 (s, 2H), 5.05 (s, 2H), 1.22 (m, 3H), 1.1 (d, 18H).
Embodiment 25
The preparation of following formula: compound
According to the method for general introduction among the embodiment 16, and use 1.6g (3.51 mM) embodiment 13 bromo ketone that obtains and the phenylmercaptan. derivant that embodiment 1 makes, use EtOAc/ hexane (1/5), behind silica gel chromatography, obtain to expect product as eluant.
1H NMR (400MHz, acetone-d
6) δ (ppm): 8.0 (d, 2H), 7.5-7.2 (m, 10H), 7.0 (d, 1H), 6.92 (d, 2H), 6.54 (d, 1H), 6.35 (dd, 1H), 6.12 (s, 1H), 5.06 (s, 2H), 1,22 (m, 3H), 1.1 (d, 18H).
Embodiment 26
The preparation of following formula: compound
According to the method for general introduction among the embodiment 16, and use 2.6g (5.82 mM) embodiment 13 bromo ketone that obtains and the phenylmercaptan. derivant that embodiment 1 makes, use EtOAc/ hexane (1/5), behind silica gel chromatography, obtain to expect product as eluant.
1HNMR (400MHz, acetone-d
6) δ (ppm): 8.0 (d, 2H), 7.4-7.2 (m, 10H), 6.94 (d, 2H), 6.84-6.74 (m, 3H), 6.24 (s, 1H), 4.85 (s, 2H), 1.23 (m, 3H), 1.1 (d, 18H).
Embodiment 27
The preparation of following formula: compound
According to the method for general introduction among the embodiment 16, and use embodiment 12 (step C) bromo ketone that obtains and the phenylmercaptan. derivant that embodiment 1 makes, use EtOAc/ hexane (1/5), behind silica gel chromatography, obtain to expect product as eluant.
1H NMR (400MHz, acetone-d
6) δ (ppm): 8.0 (d, 2H), 7.4-7.2 (m, 7H), 7.0 (m, 5H), 6.54 (d, 1H), 6.28 (dd, 1H), 6.14 (s, 1H), 5.08 (s, 2H), 1.23 (m, 3H), 1.1 (d, 18H).
Embodiment 28
The preparation of following formula: compound
According to the method for general introduction among the embodiment 16, and use embodiment 13 bromo ketone that obtains and the phenylmercaptan. derivant that embodiment 1 makes, use EtOAc/ hexane (1/5), behind silica gel chromatography, obtain to expect product as eluant.
1H?NMR(500MHz，CDCl
3)δ(ppm)8.28(s，1H)，7.82(d，2H)，7.40(m，5H)，7.22(m，5H)，6.80(d，2H)，6.40(d，1H)，6.21(dd，1H)，5.80(s，1H)，5.00(s，2H)，1.24(m，3H)，1.10(d，18H)。
Embodiment 29
The preparation of following formula: compound
According to the method for general introduction among the embodiment 16, and the phenylmercaptan. derivant of using bromo ketone that embodiment 13 obtains and embodiment 1 to make, use EtOAc/ hexane (1/5) is as eluant, behind the silicon dioxide purification, obtains expecting product.
1H?NMR(500MHz，CDCl
3)δ(ppm)8.19(s，1H)，7.82(d，2H)，7.40(m，5H)，7.24(m，5H)，6.80(d，2H)，6.64(d，1H)，6.44(d，1H)，5.84(s，1H)，5.00(s，2H)，1.23(m.3H)，1.10(m，18H)。
Embodiment 30
The preparation of following formula: compound
According to the method for general introduction among the embodiment 16, and use embodiment 12 bromo ketone that obtains and the phenylmercaptan. derivant that embodiment 1 makes, use EtOAc/ hexane (1/5), behind silica gel chromatography, obtain to expect product as eluant.
1H?NMR(500MHz，CDCl
3)δ(ppm)：8.20(s，1H)，7.81(d，2H)，7.40(m，5H)，7.02(d，2H)，6.75(d，4H)，6.36(d，1H)，6.20(dd，1H)，5.78(s，1H)，4.95(s，2H)，1.23(m，3H)，1.10(m，18H)。
Embodiment 31
The preparation of following formula: compound
According to the method for general introduction among the embodiment 16, and use embodiment 12 bromo ketone that obtains and the phenylmercaptan. derivant that embodiment 1 makes, use EtOAc/ hexane (1/5), behind silica gel chromatography, obtain to expect product as eluant.
1H?NMR(500MHz，CDCl
3)δ(ppm)：8.24(s，1H)，7.80(d，2H)，7.40(m，5H)，7.10(d，2H)，6.78(d，4H)，6.62(d，1H)，6.42(d，1H)，5.84(s，1H)，4.98(s，2H)，1.23(m，3H)，1.10(m，18H)；MSm/z?650(M
++1)。
Embodiment 32
The preparation of following formula: compound
According to the method for general introduction among the embodiment 16, and use embodiment 12 bromo ketone that obtains and the phenylmercaptan. derivant that embodiment 1 makes, use EtOAc/ hexane (1/5), behind silica gel chromatography, obtain to expect product as eluant.
1H NMR (500MHz, acetone-d
6) δ (ppm): 7.95 (d, 2H), 7.40 (m, 5H), 7.20 (d, 2H), 6.80 (m, 7H), 6.20 (s, 1H), 4.85 (s, 2H), 1.23 (m, 3H), 1.10 (m, 18H); MS m/z 616 (M
++ 1).
Embodiment 33
The preparation of following formula: compound
According to the method for general introduction among the embodiment 16, and use embodiment 12 bromo ketone that obtains and the phenylmercaptan. derivant that embodiment 1 makes, use EtOAc/ hexane (1/5), behind silica gel chromatography, obtain to expect product as eluant.
1H?NMR(500MHz，CDCl
3)δ(ppm)：7.82(d，2H)，7.40(m，5H)，7.05(d，2H)，6.95(s，1H)，6.80(d，4H)，6.52(s，1H)，5.64(s，1H)，5.00(s，2H)，1.23(m，3H)，1.10(m，18H)；MS?m/z?629(M
++1)。
Embodiment 34
The preparation of following formula: compound
According to the method for general introduction among the embodiment 16, and use embodiment 12 bromo ketone that obtains and the phenylmercaptan. derivant that embodiment 1 makes, use EtOAc/ hexane (1/5), behind silica gel chromatography, obtain to expect product as eluant.
1H?NMR(500MHz，CDCl
3)δ(ppm：8.24(s，1H)，7.80(d，2H)，7.40(m，5H)，7.10(d，2H)，6.78(d，2H)，6.76(d，2H)，6.64(d，2H)，6.45(d，2H)，5.86(s，1H)，4.98(s，2H)，1.23(m，3H)，1.10(m，18H)；MS?m/z?650(M
++1)。
Embodiment 35
The preparation of following formula: compound
According to the method for general introduction among the embodiment 16, and use embodiment 12 bromo ketone that obtains and the phenylmercaptan. derivant that embodiment 1 makes, use EtOAc/ hexane (1/5), behind silica gel chromatography, obtain to expect product as eluant.
1H?NMR(500MHz，CDCl
3)δ(ppm)：7.82(d，2H)，7.40(m，5H)，7.24(m，3H)，7.20(d，2H)，6.82(d，2H)，6.80(d，2H)，6.58(d，2H)，5.65(s，1H)，4.80(d，2H)，2.22(s，3H)，1.23(m，3H)，1.10(m，18H)。
Embodiment 36
The preparation of following formula: compound
According to the method for general introduction among the embodiment 16, and the bromo ketone that obtains of embodiment 13 and the phenylmercaptan. derivant that embodiment 1 makes, use EtOAc/ hexane (1/5) as eluant, behind silica gel chromatography, obtain to expect product.
1H?NMR(500MHz，CDCl
3)δ(ppm)：7.98(s，1H)，7.82(d，2H)，7.40(m，5H)，7.25(m，3H)，7.20(d，2H)，7.00(d，1H)，6.80(d，2H)，6.60(d，1H)，5.78(s，1H)，4.78(d，2H)，1.23(m，3H)，1.10(m，18H)。
Embodiment 37
The preparation of following formula: compound
According to the method for general introduction among the embodiment 16, and use the mixture of two kinds of phenylmercaptan. derivants that bromo ketone that embodiment 13 obtains and embodiment 1 make, use EtOAc/ hexane (1/5), behind silica gel chromatography, obtain two kinds and expect product I and II as eluant.I：
1H?NMR(500MHz，CDCl
3)δ(ppm)：7.80(d，2H)，7.40(m，5H)，7.25(m，3H)，7.16(d，2H)，7.04(s，1H)，6.80(d，2H)，6.60(s，1H)，5.78(s，1H)，4.80(d，2H)，1.23(m，3H)，1.10(m，18H)。II：
1H?NMR(500MHz，CDCl
3)δ(ppm)：7.80(d，2H)，7.65(s，1H)，7.44(d，1H)，7.40(m，5H)，7.25(m，5H)，6.96(d，1H)，6.80(m，3H)，6.00(s，1H)，5.15(s，2H)，1.23(m，3H)，1.10(m，18H)。
Embodiment 38
The preparation of following formula: compound
According to the method for general introduction among the embodiment 16, and use the bromo ketone of embodiment 12 and the phenylmercaptan. derivant that embodiment 1 makes, use EtOAc/ hexane (1/5), behind silica gel chromatography, obtain the expection product as eluant.
1H?NMR(500MHz，CDCl
3)δ(ppm)：7.80(d，2H)，7.40(m，5H)，7.14(m，2H)，6.96(m，2H)，6.84(m，2H)，6.82(d，2H)，6.70(d，1H)，5.68(s，1H)，4.86(d，2H)，1.23(m，3H)，1.10(m，18H)。
Embodiment 39
The preparation of following formula: compound
The suitable mercaptan that bromide that use embodiment 10 makes and embodiment 1 make, and use the method for summarizing among the embodiment 16, preparation following compounds: cyclohexyl derivatives: use dichloromethane/hexane (3: 1) as chromatographic eluents.
1H?NMR500MHz(CDCl
3)ppm(δ)：1.12(d，18H)，1.11-2.34(m，15H)，4.19(d，1H)，5.0(s，2H)，6.44(dd，1H)，6.54(d，1H)，6.86(m，3H)，7.25-7.72(m，7H)。Cyclopentyl derivates: use dichloromethane/hexane (2: 1) as chromatographic eluents.
1H?NMR500MHz(CDCl
3)ppm(δ)：1.12(d，18H)，1.28-2.49(m，12H)，4.18(d，1H)，5.0(s，2H)，6.45-7.77(m，12H)。
Embodiment 40
The preparation of following formula: compound
The suitable mercaptan that bromide that use embodiment 11 makes and embodiment 1 make, and use the method for summarizing among the embodiment 9, use the 30%EtOAc/ hexane as eluant, behind silica gel chromatography, obtain the expection product of yellow oily, 77% productive rate.
1H?NMR?500MHz(CDCl
3)ppm(δ)：1.00(d，3H)，1.21(d，3H)，2.30(m，1H)，4.13(d，1H)，4.99(s，2H)，6.41-7.72(m，12H)，8.02(bs，1H)，8.80(bs，1H)；MS?m/z?409(M
+)。
Embodiment 41
The routine preparation of following formula: compound
The suitable mercaptan that bromide that use embodiment 10 makes and embodiment 1 make, and adopt the method for summarizing among the embodiment 16, preparation following compounds: cyclohexyl derivatives: use dichloromethane/hexane (3: 1) as chromatographic eluents.
1H?NMR500MHz(CDCl
3)ppm(δ)：1.12(d，18H)，1.11-2.3(m，15H)，4.24(d，1H)，4.89(m，2H)，6.8-7.6(m，12H)。Cyclopentyl derivates: use dichloromethane/hexane (2: 1) as chromatographic eluents.
1H?NMR500MHz(CDCl
3)ppm(δ)：1.12(d，18H)，1.26-2.12(m，11H)，2.5(m，1H)，4.24(d，1H)，4.9(m，2H)，6.8-7.69(m，12H)。4-pyridinyl derivatives: use the 30%EtOAc/ hexane as chromatographic eluents, isolate yellow oil.
1H NMR 500MHz (CDCl
3) ppm (δ): 1.12 (d, 18H), 1.28 (m, 3H), 4.84 (q, 2H), 4.88 (s, 1H), 5.63 (s, 1H) and 6.69-8.50 (m, 16H).3-pyridinyl derivatives: use the 30%EtOAc/ hexane as chromatographic eluents, isolate yellow oil.
1H NMR 500MHz (CDCl
3) ppm (δ): 1.12 (d, 18H), 1.28-(m, 3H), 4.84 (q, 2H), 4.90 (s, 1H), 5.79 (s, 1H) and 6.70-8.50 (m, 16H).
Embodiment 42
The preparation of following formula: compound
The suitable mercaptan that bromide that use embodiment 11 makes and embodiment 1 make, and the method for general introduction among the suitable embodiment 16 use the 30%EtOAc/ hexane as eluant, behind silica gel chromatography, obtain the expection product of yellow oily.
1H?NMR?500MHz(CDCl
3)ppm(δ)：1.02(d，3H)，1.21(d，3H)，2.34(m，1H)，4.13(d，1H)，4.90(q，2H)，6.25(bs，1H)，6.79-7.70(m，12H)。
Embodiment 43
The preparation of following formula: compound
Suitable bromide that use embodiment 10 makes and quinone mercaptan (mercaptoquinol) are [according to people such as Burton, J.Chem.Soc., 1952,2193 method preparation], and the method for general introduction among the use embodiment 16, use the 30%EtOAc/ hexane as eluant, behind silica gel chromatography, obtain the expection product of orange/yellow oil.
1H NMR 500MHz (CDCl
3) ppm (δ): 1.10 (d, 18H), 1.27 (m, 3H), 6.00 (s, 1H) and 6.76-7.89 (m, 10H); MS m/z 515 (M
+).
Embodiment 44
The preparation of following formula: compound
Under blanket of nitrogen, room temperature, add lentamente in the flask of the dichloromethane solution (about 0.04M) that the thioketone that 0.1g (0.16 mM) embodiment 22 generates is housed trifluoroacetic acid (TFA) (2 * 0.062mL, 10eq).(2 * 0.05mL 4eq) and stir the gained mixture, is consumed (about 5-6 hour, monitor by TLC) until raw material to add triethyl-silicane in the reactant mixture that stirs lentamente.With the saturated NaHCO of reactant mixture impouring
3In/the frozen water, stirred 10 minutes, use dichloromethane extraction.Organic extract liquid salt water washing (2 * 50mL), use Na
2SO
4Dry also vacuum concentration obtains light yellow oil.Through purification by flash chromatography (EtOAc/Hex=1: 5), obtain buttery expection product.
1H?NMR(400MHz，CDCl
3)δ(ppm)：7.44(m，5H)，6.98(d，1H)，6.90(d，2H)，6.75(d，2H)，6.68(d，2H)，6.65(d，1H)，6.63(d，2H)，5.51(d，J＝2.3Hz，1H)，5.10(s，2H)，4.74(brs，1H)，4.32(d，J＝2.3Hz，1H)，2.77(qd，2H)，1.22(m，3H)，1.08(d，18H)，1.1(m，3H)；MS?m/z?628.5(M
++1)。
Embodiment 45
The preparation of following formula: compound
Use the method for embodiment 44, use the 10%EtOAc/ hexane, behind the silica gel chromatography purification, isolate the dihydrobenzo oxathiin that does not have the MOM protection of expection.
1HNMR (400MHz, CDCl
3) δ (ppm): 7.2-6.98 (m, 4H), 6.85 (d, 2H), 6.78 (d, 2H), 6.66 (two d, 4H), 5.5 (d, J=2.2Hz, 1H), 4.8 (s, 1H), 4.33 (d, J=2.1Hz, 1H), 1.22 (m, 3H), 1.1 (d, 18H); MS m/z 515 (M
++ 23).Also isolate other dihydrobenzo oxathiin with MOM protection.
1H?NMR(400MHz，CDCl
3)δ(ppm)：7.2-6.6(m，8H)，6.78(d，2H)，6.66(d，2H)，5.5(d，J＝2.4Hz，1H)，5.14(s，2H)，4.35(d，J＝2.1Hz，1H)，3.48(s，3H)，1.22(m，3H)，1.1(d，18H)。
Embodiment 46
The preparation of following formula: compound
Use the method for embodiment 71 (step C), slough the silicyl of the dihydrobenzo oxathiin of embodiment 45 generations, obtain product.
1H NMR (400MHz, CDCl
3) δ (ppm): 7.2-6.96 (m, 4H), 6.92 (two d, 4H), 6.82 (d, 2H), 6.6 (d, 2H), 5.52 (d, J=2.2Hz, 1H), 5.16 (s, 2H), 4.68 (br s, 1H), 4.38 (d, J=2.2Hz, 1H), 3.48 (s, 3H).
Embodiment 47
The preparation of following formula: compound
According to the method for describing among the embodiment 44, the ketone that embodiment 17 is generated is converted into the expection product, and different is to need to use 5 normal TFA and 2 normal Et
3SiH advances reaction to complete.The MOM group is removed in acid treatment (2N-HCl, 75 ℃) with gentleness, obtains expecting product.
1H?NMR(400MHz，CDCl
3)δ(ppm)：7.0(m，4H)，6.85(d，2H)，6.65(d，2H)，5.38(s，2H)；MS?m/z?343(M
++23)。
Embodiment 48
The preparation of following formula: compound
Use the method for embodiment 44, the ketone that embodiment 18 is generated is converted into the dihydrobenzo oxathiin, and different is to need to use 20 normal TFA and 15 normal Et
3SiH advances reaction to complete.Use the 10%EtOAc/ hexane as eluant,, obtain the expection product through the silica gel chromatography purification.
1H NMR (400MHz, CDCl
3) δ (ppm): 7.5-7.34 (m, 5H), 7.08 (d, 1H), 6.84 (d, 2H), 6.76 (d, 2H), 6.7 (dd, 1H), 6.67 (d, 1H), 6.68 (two d, 4H), 5.5 (d, J=2.2Hz, 1H), 5.04 (br q, 2H), 4.68 (s, 1H), 4.3 (d, J=2.2Hz, 1H), 1.22 (m, 3H), 1.1 (d, 18H); MS m/z 515 (M
++ 23).
Embodiment 49
The preparation of following formula: compound
Use the method for embodiment 44, the ketone that embodiment 19 is generated is converted into the dihydrobenzo oxathiin, and different is at 20 equivalent TFA and 2 equivalent Et
3Under the existence of SiH, will be reflected at-10 ℃ and carry out 48 hours.Use the 10%EtOAc/ hexane as eluant, behind the silica gel chromatography purification, obtain expection product [containing 20% raw material that reclaims].
1H?NMR(400MHz，CDCl
3)δ(ppm)：7.5-7.3(m，5H)，7.1-6.6(m，11H)，5.54(d，J＝1.9Hz，1H)，5.06(dd，2H)，4.32(d，1H)，3.74(s，3H)，1.22(m，3H)，1.1(d，18H)。
Embodiment 50
The preparation of following formula: compound
According to the method for general introduction among the embodiment 44, and the ketone derivatives that uses embodiment 20 to obtain, as eluant, behind the silica gel chromatography purification, obtain the expection product with the 5%EtOAc/ hexane.
1H NMR (400MHz, CDCl
3) δ (ppm): 7.46-7.32 (m, 5H), 6.84 (d, 2H), 6.78 (d, 2H), 6.66 (two d, 4H), 6.62 (d, 1H), 6.57 (d, 1H), 5.3 (d, J=2.2Hz, 1H), 4.35 (d, 1H), 2.28 (s, 3H), 1.22 (m, 3H), 1.1 (d, 18H).
Embodiment 51
The preparation of following formula: compound
According to the method for general introduction among the embodiment 44, and the ketone derivatives that uses embodiment 21 to obtain, as eluant, behind the silica gel chromatography purification, obtain the expection product with the 5%EtOAc/ hexane.
1H?NMR(400MHz，CDCl
3)δ(ppm)：7.5-7.3(m，5H)，6.98(d，1H)，6.9(d，1H)，6.76(d，2H)，6.6(m，5H)，5.51(d，J＝2.2Hz，1H)，5.1(s，2H)，4.8(s，1H)，4.32(d，1H)，2.4(s，3H)，1.22(m，3H)，1.1(d，18H)。
Embodiment 52
The preparation of following formula: compound
According to the method for general introduction among the embodiment 44, and the ketone derivatives that uses embodiment 22 to obtain, as eluant, behind the silica gel chromatography purification, obtain the expection product with the 5%EtOAc/ hexane.
1H?NMR(400MHz，CDCl
3)δ(ppm)7.5-7.3(m，5H)，6.85(d，2H)，6.78(d，2H)，6.66(m，5H)，6.56(d，1H)，5.48(d，J＝2.0Hz，1H)，5.04(br?q，2H)，4.74(br?s，1H)，4.34(d，J＝2.0Hz，1H)，2.64(q，2H)，1.3(t，3H)，1.24(m，3H)，1.1(d，18H)。
Embodiment 53
The preparation of following formula: compound
According to the method for general introduction among the embodiment 44, and the ketone derivatives that uses embodiment 23 to obtain, as eluant, behind the silica gel chromatography purification, obtain the expection product with the 5%EtOAc/ hexane.
1H NMR (400MHz, CDCl
3) δ (ppm:7.5-7.3 (m, 5H), 6.98 (d, 1H), 6.9 (d, 2H), 6.74 (d, 2H), 6.7-6.6 (three d, 5H), 5.5 (d, J=2.3Hz, 1H), 5.1 (s, 2H), 4.74 (br s, 1H), 4.32 (d, J=2.4Hz, 1H), 2.79 (m, 2H), 1.22 (m, 3H), 1.1 (d﹠amp; T, 21H); MS m/z 628.5 (M
++ 1).
Embodiment 54
The preparation of following formula: compound
According to the method for general introduction among the embodiment 44, and the ketone derivatives that uses embodiment 24 to obtain, as eluant, behind the silica gel chromatography purification, obtain the expection product with the 5%EtOAc/ hexane.
1H NMR (400MHz, CDCl
3) δ (ppm): 7.5-7.3 (m, 10H), 6.84 (d, 2H), 6.78 (d, 2H), 6.66 (two d, 4H), 6.38 (s, 2H), 5.48 (d, J=2.1Hz, 1H), 5.14 (s, 2H), 5.0 (q, 2H), 4.76 (br s, 1H), 4.32 (d, J=2.1Hz, 1H), 1.22 (m, 3H), 1.1 (d, 18H).
Embodiment 55
The preparation of following formula: compound
According to the method for general introduction among the embodiment 44, and the ketone derivatives that uses embodiment 25 to obtain, as eluant, behind the silica gel chromatography purification, obtain the expection product with the 5%EtOAc/ hexane.
1H?NMR(400MHz，CDCl
3)δ(ppm)：7.5-7.32(m，5H)，7.2-7.1(m，4H)，6.9-6.82(m，4H)，6.76-6.7(m，4H)，5.56(d，1H)，5.06(br?q，2H)，4.36(d，1H)，1.22(m，3H)，1.1(d，18H)。
Embodiment 56
The preparation of following formula: compound
According to the method for general introduction among the embodiment 44, different is to be reflected at the ketone derivatives that carried out under 0 ℃ 3 hours and used 1.7g (2.83 mM) embodiment 26 to obtain, and as eluant, behind the silica gel chromatography purification, obtains the expection product with the 5%EtOAc/ hexane.
1H?NMR(400MHz，CDCl
3)δ(ppm)：7.5-7.34(m，5H)，7.2-7.1(m，3H)，6.94(d，1H)，6.9-6.82(m，5H)，6.4(m，3H)，5.48(d，J＝1.9Hz，1H)，5.05(s，2H)，4.36(d，J＝1.9Hz，1H)，1.22(m，3H)，1.1(d，18H)。
Embodiment 57
The preparation of following formula: compound
According to the method for general introduction among the embodiment 44, the ketone derivatives that uses embodiment 27 to obtain obtains the expection product, uses the method for describing among the embodiment 71 (step C) to slough the silicyl of this product subsequently.Use the 15%EtOAc/ hexane as eluant, behind the silica gel chromatography purification, obtain oily expection product.
1H?NMR(400MHz，CDCl
3)δ(ppm)：7.5-7.32(m，5H)，7.09(d，1H)，6.9-6.8(m，6H)，6.73-6.7(m，4H)，5.52(d，1H)，5.04(br?q，2H)，4.34(d，1H)，1.22(m，3H)，1.1(d，18H)。
Embodiment 58
The preparation of following formula: compound
According to the method for general introduction among the embodiment 44, the ketone derivatives that uses embodiment 28 to obtain as eluant, behind the silica gel chromatography purification, obtains the expection product with the 5%EtOAc/ hexane.
1H?NMR(500MHz，CDCl
3)δ(ppm)：7.5-7.3(m，5H)，7.22-7.10(m，3H)，6.90-6.80(2d，4H)，6.75(d，2H)，6.55(d，2H)，5.55(d，J＝2.1Hz，1H)，5.05(d，2H)，4.40(d，J＝2.1Hz，1H)，1.22(m，3H)，1.1(d，18H)。
Embodiment 59
The preparation of following formula: compound
According to the method for general introduction among the embodiment 44, the ketone derivatives that uses embodiment 29 to obtain as eluant, behind the silica gel chromatography purification, obtains the expection product with the 5%EtOAc/ hexane.
1H?NMR(500MHz，CDCl
3)δ(ppm)：7.5-7.3(m，5H)，7.22-7.10(m，3H)，6.90-6.80(2d，4H)，6.73(d，2H)，6.64(d，2H)，5.50(d，J＝2.1Hz，1H)，5.05(d，2H)，4.43(d，J＝2.2Hz，1H)，1.23(m，3H)，1.10(d，18H)。
Embodiment 60
The preparation of following formula: compound
According to the method for general introduction among the embodiment 44, the ketone derivatives that uses embodiment 30 to obtain as eluant, behind the silica gel chromatography purification, obtains the expection product with the 5%EtOAc/ hexane.
1H?NMR(500MHz，CDCl
3)δ(ppm)：7.5-7.3(m，5H)，6.82(d，2H)，6.68(d，2H)，6.64(d，2H)，6.62(d，2H)，6.46(d，2H)，5.44(d，J＝1.9Hz，1H)，5.02(d，2H)，4.30(d，J＝2.0Hz，1H)，1.22(m，3H)，1.10(d，18H)；MS?m/z618(M
++1)。
Embodiment 61
The preparation of following formula: compound
According to the method for general introduction among the embodiment 44, the ketone derivatives that uses embodiment 31 to obtain as eluant, behind the silica gel chromatography purification, obtains the expection product with the 5%EtOAc/ hexane.
1H?NMR(400MHz，CDCl
3)δ(ppm：7.5-7.3(m，5H)，6.86(d，1H)，6.82(d，2H)，6.76(d，2H)，6.70(d，1H)，6.67(d，2H)，6.65(d，2H)，5.44(d，J＝2.0Hz，1H)，5.04(s，2H)，4.38(d，J＝1.9Hz，1H)，1.23(m，3H)，1.10(d，18H)；MS?m/z?634(M
++1)。
Embodiment 62
The preparation of following formula: compound
According to the method for general introduction among the embodiment 44, the ketone derivatives that uses embodiment 32 to obtain as eluant, behind the silica gel chromatography purification, obtains the expection product with the 5%EtOAc/ hexane.
1H?NMR(500MHz，CDCl
3)δ(ppm)：7.5-7.3(m，5H)，6.94(d，1H)，6.85(d，2H)，6.80(d，2H)，6.74(dd，2H)，6.65(m，4H)，5.43(d，J＝2.lHz，1H)，5.05(d，2H)，4.30(d，J＝2.1Hz，1H)，1.23(m，3H)，1.10(d，18H)。
Embodiment 63
The preparation of following formula: compound
According to the method for general introduction among the embodiment 44, the ketone derivatives that uses embodiment 33 to obtain as eluant, behind the silica gel chromatography purification, obtains the expection product with the 5%EtOAc/ hexane.
1H?NMR(500MHz，CDCl
3)δ(ppm)：7.5-7.3(m，5H)，6.88(s，1H)，6.84(d，2H)，6.82(d，2H)，6.70(d，2H)，6.68(d，2H)，6.66(s，1H)，5.50(d，1H)，5.05(s，2H)，4.43(d，1H)，2.35(s，3H)，1.23(m，3H)，1.10(d，18H)。
Embodiment 64
The preparation of following formula: compound
According to the method for general introduction among the embodiment 44, the ketone derivatives that uses embodiment 34 to obtain as eluant, behind the silica gel chromatography purification, obtains the expection product with the 5%EtOAc/ hexane.
1H?NMR(500MHz，CDCl
3)δ(ppm)：7.5-7.3(m，5H)，7.24(s，1H)，7.20(s，1H)，6.82(d，2H)，6.68(d，2H)，6.64(m，4H)，5.44(d，J＝2.0Hz，1H)，5.05(d，2H)，4.28(d，J＝2.3Hz，1H)，1.23(m，3H)，1.10(d，18H)。
Embodiment 65
The preparation of following formula: compound
According to the method for general introduction among the embodiment 44, the ketone derivatives that uses embodiment 35 to obtain as eluant, behind the silica gel chromatography purification, obtains the expection product with the 5%EtOAc/ hexane.
1H?NMR(500MHz，CDCl
3)δ(ppm)：7.5-7.3(m，5H)，7.05-7.20(m，4H)，6.90(d，2H)，6.88(d，2H)，6.78(d，2H)，6.70(d，1H)，6.65(d，1H)，5.30(d，J＝1.8Hz，1H)，5.05(d，2H)，4.20(d，J＝2.3Hz，1H)，1.23(m，3H)，1.10(d，18H)。
Embodiment 66
The preparation of following formula: compound
According to the method for general introduction among the embodiment 44, the ketone derivatives that uses embodiment 36 to obtain as eluant, behind the silica gel chromatography purification, obtains the expection product with the 5%EtOAc/ hexane.
1H?NMR(500MHz，CDCl
3)δ(ppm)：7.5-7.3(m，5H)，7.05-7.20(m，2H)，7.10(m，2H)，6.98(d，2H)，6.88(m，2H)，6.80(m，1H)，6.60(d，1H)，5.56(d，J＝1.8Hz，1H)，5.05(d，2H)，4.44(d，J＝2.3Hz，1H)，1.23(m，3H)，1.10(d，18H)。
Embodiment 67
The preparation of following formula: compound
According to the method for general introduction among the embodiment 44, the ketone derivatives (I) that uses embodiment 37 to obtain as eluant, behind the silica gel chromatography purification, obtains the expection product with the 5%EtOAc/ hexane.
1H?NMR(500MHz，CDCl
3)δ(ppm)：7.55(d，2H)，7.45(t，2H)，7.35(t，1H)，7.20(d，1H)，7.15(m，3H)，6.88(d，2H)，6.84(d，3H)，6.78(d，2H)，5.46(d，J＝2.1Hz，1H)，5.15(s，2H)，4.39(d，J＝2.1Hz，1H)，1.23(m，3H)，1.10(d，18H)。
Embodiment 68
The preparation of following formula: compound
According to the method for general introduction among the embodiment 44, the ketone derivatives (II) that uses embodiment 37 to obtain as eluant, behind the silica gel chromatography purification, obtains the expection product with the 5%EtOAc/ hexane.
1H?NMR(500MHz，CDCl
3)δ(ppm)：7.55(d，2H)，7.45(t，2H)，7.35(t，1H)，7.20(d，1H)，7.15(t，2H)，6.80-6.90(m，4H)，6.78(d，2H)，6.76(d，2H)，5.42(d，J＝2.1Hz，1H)，5.18(s，2H)，4.42(d，J＝2.1Hz，1H)，1.23(m，3H)，1.10(d，18H)。
Embodiment 69
The preparation of following formula: compound
According to the method for general introduction among the embodiment 44, the ketone derivatives that uses embodiment 38 to obtain as eluant, behind the silica gel chromatography purification, obtains the expection product with the 5%EtOAc/ hexane.
1H?NMR(500MHz，CDCl
3)δ(ppm)：7.36-7.50(m，5H)，6.96(d，2H)，6.80-6.90(m，4H)，6.70-6.78(m，5H)，5.42(d，J＝2.1Hz，1H)，5.18(s，2H)，4.38(d，J＝2.1Hz，1H)，1.23(m，3H)，1.10(d，18H)。
Embodiment 70
The chiral separation of following formula: compound
Use Chiralpak AD post, as eluant,, obtain the enantiomer monomer of the raceme dihydrobenzo oxathiin of embodiment 62 acquisitions by chiral chromatogram with the hexane solution of 30% isopropyl alcohol.The isomer of elder generation's eluting: [α] D=+18.44 ° (c=0.725, MeOH).The isomer of back eluting: [α] D=-18.85 ° (c=0.74, MeOH).
Embodiment 71
The routine preparation of oxygen thia hexadiene ring (THIINS)
The preparation of following formula: compound
Steps A
Under 0 ℃, through 0.2 hour, dihydrobenzo oxathiin (60mg toward embodiment 48 acquisitions, 0.1 mM) (it is crossed by azeotropy process is dry before use), triphenylphosphine (157mg, 0.6 mM) and in the mixture of 1-piperidines ethanol (0.08mL, 0.6 mM) in the anhydrous THF of 4mL drip 0.118mL (0.6 mM) diisopropyl azo-2-carboxylic acid (DIAD).With the gained pale yellow solution at stirring at room 2-3 hour.Vacuum is removed volatile component, and residue is through purification by flash chromatography (EtOAc/ hexane=1: 5,2-3%MeOH/ dichloromethane then), obtains expecting product.
1H?NMR(400MHz，CDCl
3)δ(ppm)：7.5-7.34(m，5H)，7.08(d，1H)，6.86(d，2H)，6.78-6.64(m，8H)，5.5(d，1H)，5.01(br?q，2H)，4.3(d，1H)，4.2(t，2H)，2.75(t，2H)，2.5(br?s，4H)，1.6(m，4H)，1.48(m，2H)，1.22(m，3H)，1.1(d，18H)；MS?m/z?712.4(M
++1)。
Step B
The addition product (71mg, 0.098 mM) that the past steps A that stirs generates is at 2mLEtOH/EtOAc/H
2Add in the solution among the O (7: 2: 1) 13mg (1.2eq) palladium black and ammonium formate (62mg, 10eq).The gained mixture is monitored 80 ℃ of heating and through TLC.After 3 hours, with the reactant mixture cool to room temperature, the filtration over celite filter bed, removing catalyst, and with filtrate distribution in water and ethyl acetate.Separate organic facies,, obtain expecting product through dried over mgso and vacuum concentration.
1H NMR (400MHz, CDCl
3) δ (ppm): 7.01 (d, 1H), 6.8 (d, 2H), 6.75 (d, 2H), 6.66 (two d, 4H), 6.54 (dd, 1H), 6.5 (d, 1H), 5.45 (d, J=2.3Hz, 1H), 4.28 (d, J=2.3Hz, 1H), 4.08 (t, 2H), 2.8 (t, 2H), 2.6 (br s, 4H), 1.68 (m, 4H), 1.5 (m, 2H), 1.22 (m, 3H), 1.1 (d, 18H).
Step C
At room temperature, the THF solution that adds tetrabutyl amine fluoride (3eq) in debenzylation product that generates in the step B that stirs and the mixed solution of HOAc (10eq) in mL THF.Gained solution stirring at room 2 hours, is extracted in the impouring saturated sodium bicarbonate aqueous solution and with EtOAc then.Organic layer salt water washing is through MgSO
4Drying is filtered and evaporation.The dichloromethane solution that uses 5-7%MeOH is as eluant, through the silica gel chromatography purification, obtains expecting product.
1H?NMR(400MHz，CD
3OD)δ(ppm)：6.95(d，2H)，6.92(d，1H)，6.78(d，2H)，6.71(d，2H)，6.48(d，2H)，6.47(d，1H)，6.44(dd，1H)，5.47(d，J＝2.1Hz，1H)，4.37(d，J＝2.1Hz，1H)，4.1(t，2H)，2.85(t，2H)，2.65(br?s，4H)，1.66(m，4H)，1.5(m，2H)。
Embodiment 72
The preparation of following formula: compound
Steps A
Use the method for describing among the embodiment 71 (steps A), with the dihydrobenzo oxathiin and the coupling of 1-piperidines ethanol of embodiment 53 acquisitions.Use 3%MeOH/CH
2Cl
2As eluant, behind the silica gel chromatography purification, obtain the addition product of expection.
1H NMR (400MHz, CDCl
3) δ (ppm): 6.98 (d, 1H), 6.92 (d, 2H), 6.74 (two d, 4H), 6.65 (d, 1H), 6.62 (d, 2H), 5.5 (d, 1H), 5.1 (s, 2H), 4.31 (d, 1H), 4.09 (m, 2H), 2.75 (t, 2H), 2.55 (m, 2H), 2.5 (m, 4H), 1.6 (m, 4H), 1.45 (m, 2H), 1.22 (m, 3H), 1.1 (m, 21H).
Step B
Use the method for describing among the embodiment 71 (step B), slough the benzyl of the addition product that steps A generates, obtain expecting product.
1H?NMR(400MHz，CDCl
3)δ(ppm)：6.92(d，1H)，6.89(d，2H)，6.72(d&d，4H)，6.62(d，2H)，6.5(d，1H)，5.5(d，J＝2.2Hz，1H)，4.3(d，J＝2.2Hz，1H)，4.1(m，2H)，2.8(t，2H)，2.68(m，2H)，2.58(br?s，4H)，1.64(m，4H)，1.48(m，2H)，1.2(m，3H)，1.09(d&m，21H)。
Step C
Use the method for describing among the embodiment 71 (step C), slough the silicyl of the debenzylation product that step B obtains, obtain the expection product of white solid.
1H?NMR(400MHz，CD
3OD)δ(ppm)：7.0(d，2H)，6.79(d，2H)，6.76(d，1H)，6.71(d，2H)，6.47(d，3H)，5.46(d，J＝2.2Hz，1H)，4.38(d，1H)，4.08(t，2H)，2.8(t，2H)，2.5(m，2H)，2.6(m，4H)，1.62(m，4H)，1.5(m，2H)，1.1(t，3H)；MS?m/z?493.2(M
++1)。
Embodiment 73
The preparation of following formula: compound
Steps A
Use the method for describing among the embodiment 71 (steps A), with the dihydrobenzo oxathiin and the coupling of 1-piperidines ethanol of embodiment 45 acquisitions.Use 3%MeOH/CH
2Cl
2As eluant, behind the silica gel chromatography purification, obtain the addition product of expection.
1H?NMR(400MHz，CDCl
3)δ(ppm：7.14-6.92(m，4H)，6.8(d，2H)，6.76(d，2H)，6.72(d，2H)，6.64(d，2H)，5.48(d，J＝2.2Hz，1H)，4.34(d，J＝2.1Hz，1H)，4.1(m，2H)，2.85(m，2H)，2.6(m，4H)，1.65(m，4H)，1.5(m，2H)，1.22(m，3H)，1.1(d，18H)。
Step B
Use the method for describing among the embodiment 71 (step C), slough the silicyl of the addition product that steps A obtains, obtain the expection product of white solid.
1H?NMR(400MHz，CD
3OD)δ(ppm)：7.14-6.92(m，4H)，6.06(d，2H)，6.78(d，2H)，6.72(d，2H)，6.48(d，2H)，5.48(d，J＝2.1Hz，1H)，4.44(d，1H)，4.1(t，2H)，2.78(t，2H)，2.58(brs，4H)，1.63(m，4H)，1.5(m，2H)；MS?m/z?450.2(M
++1)。
Embodiment 74
The preparation of following formula: compound
Steps A
Use the method for describing among the embodiment 71 (steps A), with the dihydrobenzo oxathiin and the coupling of 1-piperidines ethanol of embodiment 46 acquisitions.Use 3%MeOH/CH
2Cl
2, behind the silica gel chromatography purification, obtain buttery expection addition product.
1H NMR (400MHz, CDCl
3) δ (ppm): 7.14-6.94 (m, 4H), 6.96 (d, 2H), 6.84 (two d, 4H), 6.66 (d, 2H), 5.5 (d, J=2.1Hz, 1H), 5.12 (s, 2H), 4.5 (d, J=2.1Hz.1H), 4.04 (t, 2H), 3.42 (s, 3H), 2.75 (t, 2H), 2.55 (br s, 4H), 1.6 (m, 4H), 1.48 (m, 2H); MS m/z 495.2 (M
++ 1).
Step B
At room temperature, in dichloromethane, use TFA (10eq) and MeOH (6eq), slough the protecting group of the addition product (10mg, 0.02 mM) that steps A obtains, obtain expecting product.
1H NMR (400MHz, CD
3OD) δ (ppm): 7.14-6.92 (m, 4H), 6.84 (two d, 4H), 6.66 (d, 2H), 6.6 (d, 2H), 5.45 (d, J=2.2Hz, 1H), 4.45 (d, J=2.2Hz, 1H), 4.05 (t, 2H), 2.8 (t, 2H), 2.6 (br s, 4H), 1.6 (m, 4H), 1.5 (m, 2H); MS m/z450.2 (M
++ 1).
Embodiment 75
The preparation of following formula: compound
Use the method for describing among the embodiment 71 (steps A), with the 3-dioxane derivatives and the coupling of 1-piperidines ethanol of embodiment 47 acquisitions.Obtain product.
1H?NMR(400MHz，CD
3OD)δ(ppm)：7.04(d，2H)，6.98-6.84(m，4H)，6.82(d，2H)，6.74(d，1H)，6.63(d，2H)，6.56(d，2H)，5.36(d，1H)，5.33(d，J＝3.0Hz，1H)，4.02(m，2H)，2.8(m，2H)，2.6(br?s，4H)，1.62(m，4H)，1.5(m，2H)；MS?m/z?432(M
+)。
Embodiment 76
The preparation of following formula: compound
Steps A
Use the method for describing among the embodiment 71 (step C), slough the silicyl of the dihydrobenzo oxathiin of embodiment 49 generations.Obtain the expection product of white solid.
1H?NMR(400MHz，CDCl
3)δ(ppm)：7.5-7.3(m，5H)，7.2(d，1H)，6.9(d，2H)，6.88(d，2H)，6.68(m，6H)，5.53(d，J＝2.2Hz，1H)，4.33(d，J＝2.3Hz，1H)，3.75(s，3H)。
Step B
Use the method for describing among the embodiment 71 (steps A), with the desilylation product and the coupling of 1-piperidines ethanol of steps A acquisition.Use 3%MeOH/CH
2Cl
2, behind the silica gel chromatography purification, obtain the expection addition product.
1H?NMR(400MHz，CDCl
3)δ(ppm)：7.5-7.3(m，5H)，7.08(d，1H)，6.9(d，2H)，6.84(d，2H)，6.76(d，2H)，6.66(m，4H)，5.52(d，1H)，5.03(s，2H)，4.32(d，1H)，4.06(t，2H)，3.75(s，3H)，2.75(t，2H)，2.5(br?s，4H)，1.6(m，4H)，1.45(m，2H)。
Step C
Use the method for describing among the embodiment 71 (step B), the addition product debenzylation with step B generates obtains product.
1H?NMR(400MHz，CD
3OD)δ(ppm)：6.96(d，2H)，6.92(d，1H)，6.82(d，2H)，6.78(d，2H)，6.63(d，2H)，6.48(dd，1H)，6.44(d，1H)，5.5(d，J＝2.2Hz，1H)，4.42(d，J＝2.2Hz，1H)，4.08(t，2H)，3.68(s，3H)，2.78(t，2H)，2.59(br?s，4H)，1.6(m，4H)，1.48(m，2H)；MS?m/z?479.4(M
++1)。
Embodiment 77
The preparation of following formula: compound
Steps A
Use the method for describing among the embodiment 71 (steps A), with the dihydrobenzo oxathiin and the coupling of 1-piperidines ethanol of embodiment 50 acquisitions.Use 3%MeOH/CH
2Cl
2, behind the silica gel chromatography purification, obtain the addition product of expection.
1H?NMR(400MHz，CDCl
3)δ(ppm)：6.83(d，2H)，6.75(d，2H)，6.69(d，2H)，6.62(d，2H)，6.5(d，1H)，6.48(d，1H)，5.42(br?s，1H)，4.3(br?s，1H)，4.06(t，2H)，2.78(t，2H)，2.5(br?s，4H)，1.6(m，4H)，1.44(m，2H)，1.22(m，3H)，1.1(d，18H)。
Step B
Use the method for describing among the embodiment 71 (step B), slough the benzyl of the addition product of steps A generation.
Step C
Use the method for describing among the embodiment 71 (step C), slough the silicyl of the debenzylation product that step B obtains, obtain the expection product of white solid.
1H?NMR(400MHz，CD
3OD)δ(ppm)：6.94(d，2H)，6.76(d，2H)，6.7(d，2H)，6.49(d，2H)，6.4(d，1H)，6.32(d，1H)，5.43(d，J＝2.3Hz，1H)，4.4(d，J＝2.3Hz，1H)，4.08(t，2H)，2.8(t，2H)，2.6(br?s，4H)，2.18(s，3H)，1.64(m，4H)，1.5(m，2H)；MS?m/z?479.2(M
++1)。
Embodiment 78
The preparation of following formula: compound
Steps A
Use the method for describing among the embodiment 71 (steps A), with the dihydrobenzo oxathiin and the coupling of 1-piperidines ethanol of embodiment 51 acquisitions.Use 3%MeOH/CH
2Cl
2Behind the silica gel chromatography purification, obtain the addition product of expection.
Step B
Use the method for describing among the embodiment 71 (step B), slough the benzyl of the addition product of steps A generation, use 5%MeOH/CH
2Cl
2As eluant, behind the silica gel chromatography purification, obtain buttery expection product.
1H?NMR(400MHz，CDCl
3)δ(ppm)：6.9(d，2H)，6.89(d，1H)，6.73(m，4H)，6.62(d，2H)，6.52(d，1H)，5.5(d，1H)，4.3(d，1H)，4.1(br?s，2H)，2.8(br?t，2H)，2.6(br?s，4H)，2.2(s，3H)，1.6(m，4H)，1.5(m，2H)，1.22(m，3H)，1.1(d，18H)。
Step C
Use the method for describing among the embodiment 71 (step C), slough the silicyl of the debenzylation product that step B obtains, obtain the expection product of white solid.
1H NMR (400MHz, CD
3OD) δ (ppm): 7.02 (d, 2H), 6.76 (d, 2H), 6.7 (d, 2H), 6.47 (two d, 3H), 5.48 (d, J=2.3Hz, 1H), 4.38 (d, J=2.3Hz, 1H), 4.1 (t, 2H), 2.8 (t, 2H), 2.6 (br s, 4H), 2.1 (s, 3H), 1.6 (m, 4H), 1.5 (m, 2H); MS m/z 479.2 (M
++ 1).
Embodiment 79
The preparation of following formula: compound
Steps A
Use the method for describing among the embodiment 71 (steps A), with the dihydrobenzo oxathiin and the coupling of 1-piperidines ethanol of embodiment 53 acquisitions.Use 3%MeOH/CH
2Cl
2, behind the silica gel chromatography purification, obtain the addition product of expection.
Step B
Use the method for describing among the embodiment 71 (step B), slough the benzyl of the addition product of steps A generation.
Step C
Use the method for describing among the embodiment 71 (step C), slough the silicyl of the debenzylation product that step B obtains, use 5%MeOH/CH
2Cl
2After carrying out silica gel chromatography as eluant, obtain the expection product of white solid.
1H?NMR(400MHz，CD
3OD)δ(ppm)：6.94(d，2H)，6.76(d，2H)，6.7(2H，d)，6.48(d，2H)，6.41(d，1H)，6.3(d，1H)，5.44(d，J＝2.2Hz，1H)，4.4(d，J＝2.2Hz，1H)，4.08(t，2H)，2.8(t，2H)，2.62(br?s，4H)，2.6(q，2H)，1.6(m，4H)，1.45(m，2H)，1.2(t，3H)；MS?m/z493.2(M
++1)。
Embodiment 80
The preparation of following formula: compound
Steps A
Use the method for describing among the embodiment 71 (steps A), with the dihydrobenzo oxathiin and the coupling of 1-piperidines ethanol of embodiment 54 acquisitions.Use 3%MeOH/CH
2Cl
2, behind the silica gel chromatography purification, obtain the addition product of expection.
1H?NMR(400MHz，CDCl
3)δ(ppm)：7.5-7.3(m，10H)，6.86(d，2H)，6.78(d，2H)，6.74(d，2H)，6.64(d，2H)，6.38(s，2H)，5.48(d，1H)，5.14(s，2H)，5.02(q，2H)，4.32(d，1H)，4.08(t，2H)，2.8(t，2H)，2.5(br?s，4H)，1.62(m，4H)，1.5(m，2H)，1.22(m，3H)，1.1(d，18H)。
Step B
Use the method for describing among the embodiment 71 (step B), slough the benzyl of the addition product of steps A generation, use 5%MeOH/CH
2Cl
2As eluant, behind the silica gel chromatography purification, obtain buttery expection product.
Step C
Use the method for describing among the embodiment 71 (step C), slough the silicyl of the debenzylation product that step B obtains, obtain the expection product of white solid.
1H?NMR(400MHz，CD
3OD)δ(ppm)：6.94(d，2H)，6.78(d，2H)，6.72(d，2H)，6.5(d，2H)，6.06(d，1H)，6.02(d，1H)，5.42(d，J＝2.2Hz，1H)，4.33(d，J＝2.2Hz，1H)，4.09(t，2H)，2.8(t，2H)，2.6(br?s，4H)，1.64(m，4H)，1.5(m，2H)；MS?m/z?482.2(M
++1)。
Embodiment 81
The preparation of following formula: compound
Steps A
Use the method for describing among the embodiment 71 (step C), slough the silicyl of the dihydrobenzo oxathiin of embodiment 55 generations, obtain the expection product of white solid.
1H NMR (400MHz, CDCl
3) δ (ppm): 7.48-7.32 (m, 5H), 7.2-7.1 (m, 4H), 6.94-6.84 (two d, 4H), 6.7 (m, 4H), 5.56 (d, J=2.1Hz, 1H), 5.04 (br q, 2H), 4.74 (s, 1H), 4.37 (d, J=2.1Hz, 1H).
Step B
Use the method for describing among the embodiment 71 (steps A),, use 3%MeOH/CH desilylation product and the coupling of 1-piperidines ethanol that steps A obtains
2Cl
2After carrying out silica gel chromatography, obtain the expection product.
1H?NMR(400MHz，CDCl
3)δ(ppm)：7.5-7.32(m，5H)，7.2-7.04(m，4H)，6.94-6.86(m，4H)，6.76-6.66(m，4H)，5.54(br?s，1H)，5.04(br?s，2H)，4.38(br?s，1H)，4.06(t，2H)，2.76(t，2H)，2.5(br?s，4H)，1.6(m，4H)，1.42(m，2H)。
Step C
Use the method for describing among the embodiment 71 (step B), slough the benzyl of the addition product that step B generates, obtain expecting product.
1H?NMR(400MHz，CD
3OD)δ(ppm)：7.2-7.14(m，3H)，6.94(m，3H)，6.9(d，2H)，6.74(d，2H)，6.48(dd，1H)，6.45(d，1H)，5.53(d，J＝2.3Hz，1H)，4.46(d，1H)，4.06(t，2H)，2.78(t，2H)，2.58(br?s，4H)，1.62(m，4H)，1.5(m，2H)；MS?m/z?449.2(M
++1)。
Embodiment 82
The preparation of following formula: compound
Steps A
Use the method for describing among the embodiment 71 (step C), slough the silicyl of the dihydrobenzo oxathiin of embodiment 56 generations.Obtain the expection product of white solid.
1H?NMR(400MHz，CDCl
3)δ(ppm)：7.5-7.3(m，5H)，7.2-7.1(m，3H)，6.96(m，2H)，6.92(d，1H)，6.88(d，2H)，6.84(d，1H)，6.74(dd，1H)，6.66(d，2H)，5.48(d，J＝2.1Hz，1H)，5.04(s，2H)，4.37(d，J＝2.1Hz，1H)；MS?m/z?428.2(M
++1)。
Step B
Use the method for describing among the embodiment 71 (steps A),, use 3%MeOH/CH desilylation product and the coupling of 1-piperidines ethanol that steps A obtains
2Cl
2, behind the silica gel chromatography purification, obtain the expection product.
Step C
Use the method for describing among the embodiment 71 (step B), slough the benzyl of the addition product that step B generates, obtain expecting product.
1H?NMR(400MHz，CD
3OD)δ(ppm)：7.14-7.02(m，3H)，6.92(m，4H)，6.8(d，1H)，6.74(d，2H)，6.58(d，1H)，6.51(dd，1H)，5.42(br?s，1H)，4.45(br?s，1H)，4.06(t，2H)，2.78(t，2H)，2.55(br?s，4H)，1.6(m，4H)，1.5(m，2H)；MS?m/z?449.2(M
++1)。
Embodiment 83
The preparation of following formula: compound
Steps A
Under 0 ℃, add 5 equivalent m-chlorobenzoic acids (m-CPBA) in the dichloromethane solution of the dihydrobenzo oxathiin (30mg, 0.061 mM) that past well-beaten embodiment 74 (steps A) makes.Remove ice bath and with reactant mixture stirring at room 3 hours.This reactant mixture is with saturated NaHSO
3Solution-treated and restir 30 minutes.Water layer extracts with EtOAc, and MgSO is used in organic layer salt water washing
4Dry also evaporation obtains residue, and this residue need not to be further purified and promptly can be used for the next step.
1H?NMR(400MHz，CD
3OD)δ(ppm)：7.82(dd，1H)，7.67(dt，1H)，7.28(m，2H)，7.2(d，2H)，7.03(d，2H)，6.92(d，2H)，6.82(d，2H)，6.32(d，1H)，5.12(s，2H)，4.84(d，1H)，4.2(br?t，2H)，3.40(s，3H)，3.2(m，2H)，3.0(m，4H)，1.75(m，4H)，1.6(m，2H)。
Step B
According to the method for general introduction among the embodiment 74 (step B), remove the MOM protecting group.Use 5%MeOH/CH
2Cl
2As eluant, behind the silica gel chromatography purification, isolate the expection product.
1H?NMR(400MHz，CD
3OD)δ(ppm)：7.82(dd，1H)，7.64(dt，1H)，7.26(m，2H)，7.04(d，2H)，6.06(d，2H)，6.76(d，2H)，6.65(d，2H)，6.24(d，J＝1.9Hz，1H)，4.71(d，1H)，4.1(t，2H)，2，72(t，2H)，2.5(br?s，4H)，1.6(m，4H)，1.45(m，2H)；MS?m/z?481.1(M
++1)。
Embodiment 84
The preparation of following formula: compound
Steps A
Under 0 ℃, add 5 equivalent m-CPBA in the dichloromethane solution of the dihydrobenzo oxathiin (60mg) that makes toward well-beaten embodiment 73 (steps A).Remove ice bath and with reactant mixture stirring at room 3 hours.This reactant mixture is with saturated NaHSO
3Solution and saturated sodium bicarbonate solution are handled, and restir 30 minutes.Water layer extracts with EtOAc, and the organic layer of merging is with the salt water washing and use MgSO
4Dry.Evaporation removes to desolvate and obtains the oily residue, and this residue uses 3%MeOH/CH
2Cl
2As eluant, behind the silica gel chromatography purification, obtain clean product.
1H?NMR(400MHz，CD
3OD)δ(ppm)：7.85(dd，1H)，7.66(m，1H)，7.28(m，2H)，7.12(d，2H)，6.86(d，2H)，6.8(d，2H)，6.7(d，2H)，6.22(d，J＝2.1Hz，1H)，4.72(d，J＝2.3Hz，1H)，4.08(m，2H)，2.8(t，2H)，2.6(br?s，4H)，1.6(m，4H)，1.5(m，2H)，1.22(m，3H)，1.1(d，18H)；MS?m/z?637(M
++23)。
Step B
According to the method for general introduction among the embodiment 71 (step C), remove the silicyl protecting group.Use 5%MeOH/CH
2Cl
2As eluant, behind the silica gel chromatography purification, isolate the expection product.
1H NMR (400MHz, CD
3OD) δ (ppm): 7.81 (dd, 1H), 7.64 (m, 1H), 7.35 (m, 2H), 7.2 (d, 2H), 6.82 (two d, 4H), 6.6 (d, 2H), 6.28 (d, J=2.2Hz, 1H), 4.69 (d, J=2.2Hz, 1H), 4.2 (t, 2H), 3.08 (t, 2H), 2.85 (br s, 4H), 1.7 (m, 4H), 1.55 (m, 2H).
Embodiment 85
The preparation of following formula: compound
Steps A
Use the method for embodiment 83 (steps A), at room temperature, the dihydrobenzo oxathiin (20mg, 0.028 mM) that embodiment 71 (steps A) obtains is used the m-CPBA oxidation.This raw material crude product need not to be further purified and promptly can be used for the next step.
1H NMR (400MHz, CDCl
3) δ (ppm): 7.84 (d, 1H), 7.7-7.4 (m, 5H), 7.02 (d, 2H), 6.88 (dd, 1H), 6.82 (d, 2H), 6.76 (two d, 4H), 6.72 (d, 1H), 6.22 (d, J=2.2Hz, 1H), 5.18 (q, 2H), 4.28 (d, J=2.1Hz, 1H), 4.09 (t, 2H), 2.8 (t, 2H), 2.55 (br s, 4H), 1.63 (m, 4H), 1.48 (m, 2H), 1.22 (m, 3H), 1.1 (d, 18H).
Step B
Use the standard method of embodiment 71 (step B), the product deprotection that steps A is obtained obtains the product of debenzylation, and this product need not to be further purified and can use.
Step C
According to the method for general introduction among the embodiment 71 (step C), remove the silicyl protecting group.Use 5%MeOH/CH
2Cl
2As eluant, behind the silica gel chromatography purification, isolate end-product.
1H NMR (400MHz, CD
3OD) δ (ppm): 7.62 (d, 1H), 7.14 (d, 2H), 6.84 (two d, 4H), 6.68 (dd, 1H), 6.6 (d, 2H), 6.55 (d, 1H), 6.22 (d, 1H), 4.55 (d, J=2.1Hz, 1H), 4.1 (t, 2H), 2.8 (t, 2H), 2.6 (br s, 4H), 1.64 (M, 4H), 1.5 (M, 2H); MS m/z 496.1 (M
++ 1).
Embodiment 86
The preparation of following formula: compound
Steps A
At room temperature, dihydrobenzo oxathiin (100mg toward embodiment 48 generations, 0.167 add the N of triethylamine (0.07mL), catalytic amount in dichloromethane solution mM), and N-dimethyl aminopyridine (DMAP) and acetic anhydride (0.034mL, 2eq).After the gained mixture stirred 30 minutes, in the impouring saturated sodium bicarbonate.The water layer dichloromethane extraction is then through anhydrous sodium sulfate drying.Evaporating solvent obtains grease, uses the 10%EtOAc/ hexane as eluant, and this grease is carried out silica gel chromatography, obtains product.
1H?NMR(400MHz，CDCl
3)δ(ppm)：7.48-7.34(m，5H)，7.08(d，1H)，6.99(d，2H)，6.94(d，2H)，6.76(d，2H)，6.72-6.67(m，4H)，5.56(d，1H)，5.06(br?q，2H)，4.34(d，1H)，2.3(d，3H)，1.22(m，3H)，1.1(d，18H)。
Step B
According to the method for general introduction among 71 (the step C), slough the silicyl protecting group.Use 5%MeOH/CH
2Cl
2As eluant, behind the silica gel chromatography purification, isolate the expection product.
1HNMR(400MHz，CDCl
3)δ(ppm)：7.48-7.34(m，5H)，7.09(d，1H)，7.04(d，2H)，6.98(d，2H)，6.78(d，2H)，6.7(m，2H)，6.59(d，2H)，5.56(d，1H)，5.06(br?q，2H)，4.74(s，1H)，4.36(d，1H)，2.2(s，3H)。
Step C
Use the method for describing among the embodiment 71 (steps A), the product (80mg, 0.165 mM) and the coupling of 1-piperidines ethanol of the desilylation that step B is obtained.Use 3%MeOH/CH
2Cl
2After carrying out the silica gel chromatography purification, obtain the expection product.
1H?NMR(400MHz，CDCl
3)δ(ppm)：7.48-7.34(m，5H)，7.08(d，1H)，7.04(d，2H)，6.98(d，2H)，6.82(d，2H)，6.7(dd，1H)，6.68(d，1H)，6.68(d，2H)，5.58(d，J＝2.2Hz，1H)，5.05(br?q，2H)，4.36(d，J＝2.2Hz，1H)，4.05(t，2H)，2.68(t，2H)，2.5(br?s，4H)，2.25(s，3H)，1.6(m，4H)，1.45(m，2H)；MS?m/z?597.3(M
++1)。
Step D
The THF solution that adds the super hydride of 4 normal 1.0M among the anhydrous THF of the addition product that generates toward 10mg (0.017 mM) step C.After 2 hours, make it rise to room temperature (30 minutes) 0 ℃ of stirring in the gained mixture.Use H
2O/NaHCO
3With the reactant mixture hydrolysis.Water layer extracts with EtOAc, separates organic layer, and drying and evaporation obtain grease, and this grease need not to be further purified and promptly can be used for going on foot down.
Step e
Use the standard method of describing among the embodiment 71 (step B), remove the protecting group of the crude product of step D, use 5%MeOH/CH
2Cl
2As eluant, behind the silica gel chromatography purification, obtain end-product.
1H?NMR(400MHz，CD
3OD)δ(ppm)：6.92(d，1H)，6.83(d，2H)，6.82(d，2H)，6.65(d，2H)，6.58(d，2H)，6.46(dd，1H)，6.42(d，1H)，5.44(d，J＝2.1Hz，1H)，4.38(d，1H，J＝2.3Hz，1H)，4.04(t，2H)，2.78(t，2H)，2.6(br?s，4H)，1.6(m，4H)，1.5(m，2H)；MS?m/z?465(M
++1)。
Embodiment 87
The preparation of following formula: compound
Steps A
Use the method for describing among the embodiment 71 (steps A), product and the coupling of 1-piperidines ethanol of the desilylation that embodiment 57 is obtained, use 3%MeOH/CH
2Cl
2After carrying out the silica gel chromatography purification, obtain the expection product.
Step B
The method of using embodiment 71 (step B) to describe is sloughed the benzyl of the addition product that steps A generates, and obtains expecting product.
1H?NMR(400MHz，CD
3OD)δ(ppm)：6.98-6.76(m，9H)，6.5(dd，1H)，6.46(d，1H)，5.52(d，J＝2.3Hz，1H)，4.5(d，1H)，4.05(t，2H)，2.80(t，2H)，2.62(br?s，4H)，1.62(m，4H)，1.5(m，2H)；MS?m/z?466.2(M
+)。
Embodiment 88
The chiral separation of following formula: compound
On Chiralpak AD post, the hexane solution that uses 20%EtOH splits the raceme dihydrobenzo oxathiin that embodiment 81 (step C) obtains as eluant by chiral chromatogram.The isomer of elder generation's eluting: [α]
D=+33.43 ° (c=1.205, MeOH).The isomer of back eluting: [α]
D=-34.2 ° (c=1.09, MeOH).
Embodiment 89
The chiral separation of following formula: compound
On Chiralpak AD post, the hexane solution that uses 20%EtOH splits the raceme dihydrobenzo oxathiin that embodiment 82 (step C) obtains as eluant by chiral chromatogram.The isomer of elder generation's eluting: [α]
D=+32.4 ° (c=1.36, MeOH).The isomer of back eluting: [α]
D=-31.3 ° (c=1.37, MeOH).
Embodiment 90
The preparation of following formula: compound
Steps A
Use the method for describing among the embodiment 71 (step C), slough the silicyl of the dihydrobenzo oxathiin of embodiment 58 generations.Obtain the expection product of white solid.
1H?NMR(500MHz，CDCl
3)δ(ppm)：7.5-7.3(m，5H)，7.2-7.1(m，3H)，6.85(2d，4H)，6.68(d，2H)，6.55(d，2H)，5.55(d，1H)，5.04(s，2H)，4.40(d，1H)。
Step B
Use the method for describing among the embodiment 71 (steps A), with the desilylation product and the coupling of 1-piperidines ethanol of steps A acquisition.Use 3%MeOH/CH
2Cl
2After carrying out chromatogram purification, obtain the expection product.
Step C
Under hydrogen balloon, addition product (80mg, 0.144 mM), 20mg palladium black and the mixture of 5 AcOH in 4mL ethanol that step B is generated stir and monitor through TLC.After 18 hours,,, add saturated sodium bicarbonate aqueous solution in the filtrate and neutralize, and use ethyl acetate extraction to remove catalyst with reactant mixture filtration over celite filter bed.Separate organic layer,, obtain expecting product through dried over mgso and vacuum concentration.
1H?NMR(500MHz，CD
3OD)δ(ppm)：7.20-7.02(m，3H)，6.92(m，4H)，6.78(d，2H)，6.30(d，2H)，5.55(d，J＝2.1Hz，1H)，4.50(d，J＝2.3Hz，1H)，4.06(t，2H)，2.78(t，2H)，2.55(br?s，4H)，1.6(m，4H)，1.5(m，2H)；MS?m/z?467(M
++1)。
Embodiment 91
The preparation of following formula: compound
Steps A
Use the method for describing among the embodiment 71 (step C), slough the silicyl of the dihydrobenzo oxathiin of embodiment 59 generations.Obtain the expection product of white solid.
1H?NMR(500MHz，CDCl
3)δ(ppm)：7.5-7.3(m，5H)，7.2-7.1(m，3H)，6.95(d，2H)，6.90(d，1H)，6.85(d，2H)，6.70(d，2H)，6.65(d，1H)，5.50(d，1H)，5.04(s，2H)，4.42(d，1H)。
Step B
Use the method for describing among the embodiment 71 (steps A), product and the coupling of 1-piperidines ethanol of the desilylation that steps A is obtained, use 3%MeOH/CH
2Cl
2After carrying out the silica gel chromatography purification, obtain the expection product.
Step C
Use the method for describing among the embodiment 71 (step B), slough the benzyl of the addition product that generates among the step B, obtain expecting product.
1H?NMR(500MHz，CD
3OD)δ(ppm)：7.14-7.02(m，3H)，6.92(d，2H)，6.85(d，2H)，6.74(d，2H)，6.58(d，1H)，6.41(d，1H)，5.52(d，J＝2.3Hz，1H)，4.55(d，J＝2.3Hz，1H)，4.06(t，2H)，2.78(t，2H)，2.55(br?s，4H)，1.6(m，4H)，1.5(m，2H)；MS?m/z?483(M
++1)。
Embodiment 92
The preparation of following formula: compound
Steps A
Use the method for describing among the embodiment 71 (steps A),, use 3%MeOH/CH dihydrobenzo oxathiin and the coupling of 1-piperidines ethanol that embodiment 60 obtains
2Cl
2Behind the silica gel chromatography purification, obtain the expection product.
1H?NMR(500MHz，CDCl
3)δ(ppm)：7.5-7.3(m，5H)，6.80(d，2H)，6.70(2d，4H)，6.60(d，2H)，6.40(2d，2H)，5.40(s，1H)，4.90(d，2H)，4.20(s，1H)，4.08(t，2H)，2.8(t，2H)，2.5(br?s，4H)，1.62(m，4H)，1.5(m，2H)，1.22(m，3H)，1.1(d，18H)。
Step B
Use the method for describing among the embodiment 71 (step B), slough the benzyl of the addition product of steps A generation.
Step C
Use the method for describing among the embodiment 71 (step C), slough the silicyl of the debenzylation product that step B obtains, obtain the expection product of white solid.
1H?NMR(500MHz，CD
3OD)δ(ppm)：6.93(d，3H)，6.78(d，2H)，6.69(d，2H)，6.50(d，2H)，6.28(m，1H)，5.46(d，J＝1.8Hz，1H)，4.39(d，J＝2.2Hz，1H)，4.05(t，2H)，2.8(t，2H)，2.6(br?s，4H)，1.64(m，4H)，1.5(m，2H)；MS?m/z?482.2(M
++1)。
Embodiment 93
The preparation of following formula: compound
Steps A
Use the method for describing among the embodiment 71 (steps A),, use 3%MeOH/CH dihydrobenzo oxathiin and the coupling of 1-piperidines ethanol that embodiment 61 obtains
2Cl
2After carrying out the silica gel chromatography purification, obtain the expection product.
1H?NMR(500MHz，CDCl
3)δ(ppm)：7.5-7.3(m，5H)，6.85(m，3H)，6.70(d，4H)，6.63(d，2H)，6.60(d，1H)，5.42(s，1H)，5.02(d，2H)，4.40(s，1H)，4.08(t，2H)，2.8(t，2H)，2.5(br?s，4H)，1.62(m，4H)，1.5(m，2H)，1.22(m，3H)，1.1(d，18H)。
Step B
Use the method for describing among the embodiment 71 (step B), slough the benzyl of the addition product that steps A generates, obtain expecting product.
1H?NMR(500MHz，CD
3OD)δ(ppm)：6.82(d，2H)，6.78(d，H)，6.70(2d，4H)，6.62(d，2H)，6.58(d，1H)，5.40(d，1H)，4.30(d，1H)，4.06(t，2H)，2.78(t，2H)，2.55(br?s，4H)，1.6(m，4H)，1.5(m，2H)；MS?m/z?655(M
++1)。
Step C
Use the method for describing among the embodiment 71 (step C), slough the silicyl of the debenzylation product that step B obtains, obtain the expection product of white solid.
1H?NMR(500MHz，CD
3OD)δ(ppm)：6.92(d，2H)，6.75(d，2H)，6.68(d，2H)，6.60(d，1H)，6.50(d，2H)，6.42(d，1H)，5.42(d，J＝2.2Hz，1H)，4.42(d，J＝2.3Hz，1H)，4.07(t，2H)，2.78(t，2H)，2.55(brs，4H)，1.62(m，4H)，1.48(m，2H)；MSm/z?499(M
++1)。
Embodiment 94
The preparation of following formula: compound
Steps A
Use the method for describing among the embodiment 71 (steps A),, use 3%MeOH/CH dihydrobenzo oxathiin and the coupling of 1-piperidines ethanol that embodiment 62 obtains
2Cl
2After carrying out the silica gel chromatography purification, obtain the expection product.
Step B
Use the method for describing among the embodiment 71 (step B), slough the benzyl of the addition product of steps A generation.
Step C
Use the method for describing among the embodiment 71 (step C), slough the silicyl of the debenzylation product that step B obtains, use 5%MeOH/CH
2Cl
2As eluant, behind the silica gel chromatography purification, obtain the expection product of white solid.
1H NMR (500MHz, acetone-d
6) δ (ppm): 7.04 (d, 2H), 6.90 (dd, 3H), 6.72 (d, 2H), 6.64 (d, 1H), 6.59 (d, 2H), 6.57 (dd, 1H), 5.44 (d, J=2.3Hz, 1H), 4.52 (d, J=2.1Hz, 1H), 4.08 (t, 2H), 2.8 (t, 2H), 2.62 (br s, 4H), 2.6 (q, 2H), 1.6 (m, 4H), 1.45 (m, 2H), 1.2 (t, 2H); MS m/z 465 (M
++ 1).
Embodiment 95
The preparation of following formula: compound
Steps A
Use the method for describing among the embodiment 71 (steps A),, use 3%MeOH/CH dihydrobenzo oxathiin and the coupling of 1-piperidines ethanol that embodiment 63 obtains
2Cl
2After carrying out the silica gel chromatography purification, obtain the expection product.
Step B
Use the method for describing among the embodiment 71 (step B), slough the benzyl of the addition product of steps A generation.
Step C
Use the method for describing among the embodiment 71 (step C), slough the silicyl of the debenzylation product that step B obtains, use 5%MeOH/CH
2Cl
2As eluant, behind the silica gel chromatography purification, obtain the expection product of white solid.
1H NMR (500MHz, acetone-d
6) δ (ppm): 7.00 (d, 2H), 6.85 (s, 1H), 6.80 (d, 2H), 6.78 (d, 2H), 6.59 (d, 2H), 6.52 (s, 1H), 5.49 (d, J=2.3Hz, 1H), 4.65 (d, J=2.2Hz, 1H), 4.08 (t, 2H), 2.8 (t, 2H), 2.62 (br s, 4H), 2.6 (q, 2H), 1.6 (m, 4H), 1.45 (m, 2H), 1.2 (t, 2H); MS m/z479 (M
++ 1).
Embodiment 96
The preparation of following formula: compound
Steps A
Use the method for describing among the embodiment 71 (steps A),, use 3%MeOH/CH dihydrobenzo oxathiin and the coupling of 1-piperidines ethanol that embodiment 64 obtains
2Cl
2After carrying out the silica gel chromatography purification, obtain the expection product.
1H?NMR(500MHz，CDCl
3)δ(ppm)：7.5-7.3(m，5H)，7.20(s，1H)，6.85(d，2H)，6.70(2d，4H)，6.63(d，2H)，6.60(s，1H)，5.42(s，1H)，5.02(q，2H)，4.30(s，1H)，4.08(t，2H)，2.8(t，2H)，2.5(br?s，4H)，1.62(m，4H)，1.5(m，2H)，1.22(m，3H)，1.1(d，18H)。
Step B
Use the method for describing among the embodiment 71 (step B), slough the benzyl of the addition product that steps A generates, obtain expecting product.
1H NMR (500MHz, acetone-d
6) δ (ppm): 7.10 (s, 1H), 6.98 (d, 2H), 6.82 (d, 2H), 6.78 (d, 2H), 6.70 (d, 2H), 6.68 (s, 1H), 5.50 (d, 1H), 4.50 (d, 1H), 4.06 (t, 2H), 2.78 (t, 2H), 2.55 (br s, 4H), 1.6 (m, 4H), 1.5 (m, 2H).
Step C
Use the method for describing among the embodiment 71 (step C), slough the silicyl of the debenzylation product that step B obtains, obtain the expection product of white solid.
1H NMR (500MHz, acetone-d
6) δ (ppm): 7.12 (s, 1H), 7.02 (d, 2H), 6.80 (dd, 4H), 6.69 (s, 1H), 6.60 (d, 2H), 6.42 (d, 1H), 5.55 (d, J=2.3Hz, 1H), 4.54 (d, J=2.1Hz, 1H), 4.07 (t, 2H), 2.78 (t, 2H), 2.55 (br s, 4H), 1.62 (m, 4H), 1.48 (m, 2H); MS m/z 499 (M
++ 1).
Embodiment 97
The preparation of following formula: compound
Steps A
Use the method for describing among the embodiment 71 (step C), slough the silicyl of the dihydrobenzo oxathiin of embodiment 65 generations, obtain the expection product of white solid.
1H?NMR(500MHz，CDCl
3)δ(ppm)：7.5-7.3(m，5H)，7.2-7.1(m，5H)，6.95(m，3H)，6.64-6.70(m，2H)，5.46(d，J＝1.8Hz，1H)，5.04(s，2H)，4.42(d，J＝2.0Hz，1H)。
Step B
Use the method for describing among the embodiment 71 (steps A), product and the coupling of 1-piperidines ethanol of the desilylation that steps A is obtained, use 3%MeOH/CH
2Cl
2After carrying out the silica gel chromatography purification, obtain the expection product.
Step C
Use the method for describing among the embodiment 71 (step B), slough the benzyl of the addition product that step B generates, obtain expecting product.
1H?NMR(500MHz，CD
3OD)δ(ppm)：7.00-7.12(m，6H)，6.90(d，2H)，6.75(d，2H)，6.42(s，1H)，5.42(d，J＝2.1Hz，1H)，4.48(d，J＝2.3Hz，1H)，4.06(t，2H)，2.78(t，2H)，2.55(br?s，4H)，1.6(m，4H)，1.5(m，2H)；MS?m/z?463(M
++1)。
Embodiment 98
The preparation of following formula: compound
Steps A
Use the method for describing among the embodiment 71 (step C), slough the silicyl of the dihydrobenzo oxathiin of embodiment 66 generations, obtain the expection product of white solid.
1H?NMR(500MHz，CDCl
3)δ(ppm)：7.5-7.3(m，5H)，7.2-7.1(m，3H)，6.95(d，2H)，6.92(d，2H)，6.90(d，1H)，6.78(d，1H)，6.70(d，2H)，5.52(d，J＝2.1Hz，1H)，5.04(s，2H)，4.46(d，J＝2.2Hz，1H)。
Step B
Use the method for describing among the embodiment 71 (steps A), 3%MeOH/CH is used in the product and the coupling of 1-piperidines ethanol of the desilylation that steps A is obtained
2Cl
2After carrying out the silica gel chromatography purification, obtain the expection product.
Step C
Use the method for describing among the embodiment 71 (step B), slough the benzyl of the addition product of step B generation, obtain the expection product.
1H?NMR(500MHz，CD
3OD)δ(ppm)：7.05-7.15(m，5H)，6.90(d，2H)，6.79(d，2H)，6.65(d，1H)，6.55(d，1H)，5.50(d，J＝2.1Hz，1H)，4.62(d，J＝2.3Hz，1H)，4.10(t，2H)，2.80(t，2H)，2.60(br?s，4H)，1.6(m，4H)，1.5(m，2H)；MS?m/z?483(M
+1)。
Embodiment 99
The preparation of following formula: compound
Steps A
Use the method for describing among the embodiment 71 (step C), slough the silicyl of the dihydrobenzo oxathiin of embodiment 67 generations, obtain the expection product of white solid.
1H?NMR(500MHz，CDCl
3)δ(ppm)：7.5-7.3(m，5H)，7.2-7.1(m，3H)，7.08(s，1H)，6.95(d，2H)，6.86(m，3H)，6.70(d，2H)，5.42(d，J＝2.1Hz，1H)，5.14(s，2H)，4.40(d，J＝2.0Hz，1H)。
Step B
Use the method for describing among the embodiment 71 (steps A), product and the coupling of 1-piperidines ethanol of the desilylation that steps A is obtained, use 3%MeOH/CH
2Cl
2After carrying out the silica gel chromatography purification, obtain the expection product.
Step C
Use the method for describing among the embodiment 71 (step B), slough the benzyl of the addition product of step B generation, obtain the expection product.
1H?NMR(500MHz，CD
3OD)δ(ppm)：7.05-7.15(m，3H)，6.95(m，3H)，6.90(d，2H)，6.75(d，2H)，6.72(s，1H)，5.45(d，J＝2.0Hz，1H)，4.52(d，J＝2.3Hz，1H)，4.10(t，2H)，2.80(t，2H)，2.60(br?s，4H)，1.6(m，4H)，1.5(m，2H)；MS?m/z?483(M
++1)。
Embodiment 100
The preparation of following formula: compound
Steps A
Use the method for describing among the embodiment 71 (step C), slough the silicyl of the dihydrobenzo oxathiin of embodiment 68 generations, obtain the expection product of white solid.
1H?NMR(500MHz，CDCl
3)δ(ppm)：7.5-7.3(m，5H)，7.2-7.1(m，3H)，6.92-6.80(m，5H)，6.78(d，2H)，6.70(d，2H)，5.40(d，J＝2.1Hz，1H)，5.20(s，2H)，4.46(d，J＝2.0Hz，1H)。
Step B
Use the method for describing among the embodiment 71 (steps A), the product and the coupling of 1-piperidines ethanol of the desilylation that steps A is obtained.Use 3%MeOH/CH
2Cl
2After carrying out the silica gel chromatography purification, obtain the expection product.
Step C
Use the method for describing among the embodiment 71 (step B), slough the benzyl of the addition product that step B generates, obtain expecting product.
1H?NMR(500MHz，CD
3OD)δ(ppm)：7.05-7.15(m，3H)，6.95(d，2H)，6.90(d，2H)，6.80(d，1H)，6.75(d，2H)，6.70(d，1H)，5.38(d，J＝1.8Hz，1H)，4.56(d，J＝2.1Hz，1H)，4.06(t，2H)，2.78(t，2H)，2.60(br?s，4H)，1.6(m，4H)，1.5(m，2H)；MS?m/z?483(M
++1)。
Embodiment 101
The chiral separation of following formula: compound
On Chiralpak AD post, the hexane solution that uses 20%EtOH splits the raceme dihydrobenzo oxathiin that embodiment 100 (step C) obtains as eluant by chiral chromatogram.The isomer of elder generation's eluting: [α]
D=+26.09 ° (c=1.025, MeOH).The isomer of back eluting: [α]
D=-25.44 ° (c=0.95, MeOH).
Embodiment 102
The preparation of following formula: compound
Steps A
Use the method for describing among the embodiment 71 (step C), slough the silicyl of the dihydrobenzo oxathiin of embodiment 69 acquisitions.Obtain the expection product of white solid.
1H?NMR(500MHz，CDCl
3)δ(ppm)：7.5-7.3(m，5H)，6.95(d，2H)，6.90(m，3H)，6.85(m，3H)，6.74(dd，1H)，6.70(d，2H)，5.45(d，J＝1.9Hz，1H)，5.05(s，2H)，4.35(d，J＝2.1Hz，1H)。
Step B
Use the method for describing among the embodiment 71 (steps A), the product and the coupling of 1-piperidines ethanol of the desilylation that steps A is obtained.Use 3%MeOH/CH
2Cl
2After carrying out the silica gel chromatography purification, obtain the addition product of expection, this product need not further can use.
Step C
Use the method for describing among the embodiment 71 (step B), slough the benzyl of the addition product of step B generation, obtain the expection product.
1H?NMR(500MHz，CD
3OD)δ(ppm)：6.98(d，2H)，6.94(m，2H)，6.80(m，5H)，6.60(d，1H)，6.75(dd，1H)，5.40(d，J＝1.8Hz，1H)，4.50(d，J＝2.1Hz，1H)，4.08(t，2H)，2.78(t，2H)，2.60(br?s，4H)，1.6(m，4H)，1.5(m，2H)；MS?m/z?466(M
++1)。
Embodiment 103
The chirality preparation of following formula: compound
(+) isomer
Steps A
Use the method for describing among the embodiment 71 (steps A), (+)-dihydrobenzo oxathiin and the coupling of 1-piperidines ethanol of the first eluting that embodiment 70 is obtained, use 3%MeOH/CH
2Cl
2After carrying out the silica gel chromatography purification, obtain the expection product.
Step B
Use the method for describing among the embodiment 71 (step B), slough the benzyl of the addition product of steps A generation.
Step C
Use the method for describing among the embodiment 71 (step C), slough the silicyl of the debenzylation product that step B obtains, use 5%MeOH/CH
2Cl
2As eluant, behind the silica gel chromatography purification, obtain the expection product of white solid.
1H NMR (500MHz, acetone-d
6) δ (ppm): 6.90 (d, 2H), 6.78 (d, 1H), 6.72 (d, 2H), 6.70 (d, 2H), 6.60 (d, 1H), 6.50 (d, 1H), 6.48 (d, 2H), 5.38 (d, J=2.0Hz, 1H), 4.38 (d, J=2.3Hz, 1H), 4.08 (t, 2H), 2.8 (t, 2H), 2.62 (br s, 4H), 2.6 (q, 2H), 1.6 (m, 4H), 1.45 (m, 2H), 1.2 (t, 2H); MS m/z 465 (M
++ 1); [α]
D=+27.68 ° (c=0.49, MeOH).
Embodiment 104
The chirality preparation of following formula: compound
(-) isomer
Steps A
Use the method for describing among the embodiment 71 (steps A), (-)-dihydrobenzo oxathiin and the coupling of 1-piperidines ethanol of the back eluting that embodiment 70 is obtained, use 3%MeOH/CH
2Cl
2After carrying out the silica gel chromatography purification, obtain the expection product.
Step B
Use the method for describing among the embodiment 71 (step B), slough the benzyl of the addition product of steps A generation.
Step C
Use the method for describing among the embodiment 71 (step C), slough the silicyl of the debenzylation product that step B obtains, use 5%MeOH/CH
2Cl
2As eluant, behind the silica gel chromatography purification, obtain the expection product of white solid.
1H NMR (500MHz, acetone-d
6) δ (ppm): 6.90 (d, 2H), 6.78 (d, 1H), 6.72 (d, 2H), 6.70 (d, 2H), 6.60 (d, 1H), 6.50 (d, 1H), 6.48 (d, 2H), 5.38 (d, J=2.0Hz, 1H), 4.38 (d, J=2.3Hz, 1H), 4.08 (t, 2H), 2.8 (t, 2H), 2.62 (br s, 4H), 2.6 (q, 2H), 1.6 (m, 4H), 1.45 (m, 2H), 1.2 (t, 2H); MS m/z 465 (M
++ 1); [α]
D=-26.33 ° (c=0.515, MeOH).
Embodiment 105
The routine preparation of following formula: compound
Steps A: reductive ring closure
Under-23 ℃, blanket of nitrogen, add the pure trifluoroacetic acid (TFA) of 68 μ L (0.087 mM) in the solution of cyclopenta-thioketone in the 1mL dichloromethane that generates toward 102.2mg (0.17 mM) embodiment 41 that stirs.Add 41.4 μ L (0.259 mM) pure triethyl-silicane in this reactant mixture under-23 ℃ that stir lentamente and with gained mixture restir 3 hours.This reactant mixture is assigned to ethyl acetate/saturated NaHCO
3In/ice/the saline and separate organic facies, use the salt water washing,, filter also evaporation through anhydrous sodium sulfate drying.Residue use dichloromethane/hexane (1: 1) through the silica gel chromatography purification, obtains cis-cyclopenta-dihydrobenzo oxathiin derivant as eluant.
1H?NMR?500MHz(CDCl
3)ppm(δ)：1.12(d，18H)，1.26-2.12(m，12H)，2.5(m，1H)，4.24(d，1H)，4.9(m，2H)，6.8-7.69(m，12H)。
The cyclohexyl derivatives that makes with embodiment 41 is as raw material, and uses said method, use dichloromethane-hexane (1: 1) to carry out the silica gel chromatography purification after, prepare corresponding cis-cyclohexyl-benzo oxathiin.
1H?NMR?500MHz(CDCl
3)ppm(δ)：1.14(d，18H)，1.11-1.9(m，14H)，3.2(t，1H)，5.03(s，2H)，5.44(d，J＝2.5Hz，1H)，6.66-7.47(m，12H)。
Step B: desilylation
Under 0 ℃, order adds the THF solution of 13.3 μ l (0.234 mM) acetic acid and 171 μ L (0.171 mM) 1M tetrabutyl amine fluoride in the solution of 89.6mg (0.156 mM) cis-cyclopentyl derivates in 1mL THF that makes toward the steps A that stirs.With this mixture 0 ℃ stir 0.5 hour after, be assigned in ethyl acetate/2N HCl/ ice/saline and separate organic facies, use the salt water washing, through anhydrous sodium sulfate drying, filtration is also evaporated.Residue uses dichloromethane-ethyl acetate (50: 1) as eluant, through the silica gel chromatography purification, obtains phenol derivatives.
1H?NMR?500MHz(CDCl
3)ppm(δ)：1.32-1.94(m，9H)，3.51(dd，J＝5.5，2.5Hz，1H)，5.03(s，2H)，5.42(d，J＝2.3Hz，1H)，6.67-7.47(m，12H)。
The cyclohexyl derivatives that makes with front embodiment is as raw material, and uses said method, prepares corresponding cis-cyclohexyl-benzo oxathiin phenol.
1H?NMR?500MHz(CDCl
3)ppm(δ)：1.11-1.93(m，11H)，3.23(t，J＝3Hz，1H)，5.03(s，2H)，5.44(d，J＝2.3Hz，1H)，6.66-7.47(m，12H)。
Step C:Mitsunobu reaction
Under 0 ℃, add 87.4 μ l (0.444 mM) pure diisopropyl azo-2-carboxylic acids (DIAD) in step B makes above the 56.3mg (0.135 mM) that stirs cis-cyclopentyl derivates, 53.6 μ L (0.404 mM) 1-piperidines ethanol and the solution of 123.5mg (0.47 mM) triphenylphosphine in the anhydrous THF of 1mL.Remove ice-water bath and with this mixture restir 6 hours.Be assigned to this mixture in ethyl acetate/2N HCl/ ice/saline and separate organic facies, use the salt water washing,, filter also evaporation through anhydrous sodium sulfate drying.Residue uses ethyl acetate-methanol (9: 1) as eluant, through the silica gel chromatography purification, obtains addition product.
1H?NMR?500MHz(CDCl
3)ppm(δ)：1.33-2.0(m，15H)，2.56(m，4H)，2.82(t，J＝6Hz，2H)，3.51(dd，J＝5.4，2.4Hz，1H)，4.16(t，J＝6Hz，2H)，5.02(s，2H)，5.42(d，J＝2.3Hz，1H)，6.66-7.46(m，12H)。
The cyclohexyl derivatives that makes with front embodiment is as raw material, and uses said method, prepares corresponding cis-cyclohexyl-benzo oxathiin addition product.
1H?NMR500MHz(CDCl
3)ppm(δ)：1.11-1.93(m，17H)，2.6(m，4H)，2.87(m，2H)，3.2(d，J＝2.5Hz，1H)，4.2(m，2H)，5.02(s，2H)，5.44(d，J＝2.1Hz，1H)，6.65-7.46(m，12H)。
Step D: debenzylation
Cis-cyclopentyl derivates, 14.7mg (0.014 mM) palladium black and the mixture of 87.1mg (0.138 mM) ammonium formate in 2mL ethanol-ethyl acetate-water (7: 2: 1) that step C above the 36.6mg (0.0069 mM) that stirs is made heated 2 hours at 80 ℃.With this mixture filtration over celite, use the ethyl acetate thorough washing, filtrate distribution in ethyl acetate/saturated sodium bicarbonate/saline and separate organic facies, is used the salt water washing, through anhydrous sodium sulfate drying, filter also evaporation.Residue uses ethyl acetate-methanol (9: 1) as eluant, through the silica gel chromatography purification, obtains end-product.
1H NMR 500MHz (CDCl
3) ppm (δ): 1.33-2.0 (m, 15H), 2.6 (m, 4H), 2.88 (m, 2H), 3.48 (t, J=2.3Hz, 1H), 4.18 (m, 2H), 5.38 (d, J=2.3Hz, 1H), 6.5 (m, 1H), 6.63 (d, 2.9Hz, 1H), 6.74 (d, J=8.7Hz, 1H), 6.89 (d, J=8.7Hz, 2H) and 7.34 (d, J=8.7Hz, 2H).
The cyclohexyl derivatives that makes with front embodiment is as raw material, and uses said method, prepares corresponding cis-cyclohexyl-benzo oxathiin addition product.
1H NMR500MHz (CDCl
3) ppm (δ): 1.00-1.90 (m, 18H), 2.6 (m, 4H), 2.81 (t, 2H), 3.19 (t, J=3.0Hz, 1H), 4.18 (m, 2H), 5.38 (d, J=2.3Hz, 1H), 6.43 (m, 1H), 6.62 (d, J=3.0Hz, 1H), 6.68 (d, J=8.7Hz, 1H), 6.87 (d, J=8.7Hz, 2H) and 7.34 (d, J=8.7Hz, 2H); MS m/z 454 (M
+).
Embodiment 106
The preparation of following formula: compound
Steps A: reductive ring closure
(0.0208g 0.049mmol) is raw material and the method for using general introduction among the embodiment 105 (steps A) to the isopropyl addition product that uses embodiment 42 to make, and after 6 hours 20 minutes, separates crude product-23 ℃ of stirrings.Use the 30%EtOAc/ hexane as eluant, behind the silica gel chromatography purification, obtain the expection product of yellow oily.
1H?NMR?500MHz(CDCl
3)ppm(δ)：0.95(d，3H)，0.98(d，3H)，1.95(m，1H)，3.30(t，J＝3Hz，1H)，5.03(s，2H)，5.42(d，J＝2.6Hz，1H)，6.66-7.47(m，12H)。
Step B:Mitsunobu reaction
Use the method for describing among the embodiment 105 (step C), with dihydrobenzo oxathiin and the coupling of 1-piperidines ethanol that top steps A makes, different is to make reaction be warming to room temperature from 0 ℃ through 3.5 hours.Use 10%MeOH/CH
2Cl
2After carrying out the silica gel chromatography purification as eluant, obtain the expection product of light yellow oily.
1H?NMR?500MHz(CDCl
3)ppm(δ)：0.95(d，3H)，0.98(d，3H)，1.50-1.68(m，6H)，1.95(m，1H)，2.60(m，4H)，2.86(t，2H)，3.30(t，J＝3Hz，1H)，4.20(t，2H)，5.03(s，2H)，5.42(d，J＝2.6Hz，1H)，6.66-7.49(m，12H)。
Step C: debenzylation
The chemical compound that step B makes above using is as raw material and use the method for summarizing among the embodiment 105 (step D), uses 10%MeOH/CH
2Cl
2As eluant, behind silica gel chromatography, make corresponding cis-isopropyl-benzo oxathiin addition product.
1H NMR 500MHz (CDCl
3) ppm (δ): 0.95 (d, 3H), 0.98 (d, 3H), 1.50-1.68 (m, 6H), 1.95 (m, 1H), 2.60 (m, 4H), 2.86 (t, 2H), 3.26 (t, J=3.0Hz, 1H), 4.20 (t, 2H), 5.37 (d, J=2.5Hz, 1H), 6.47 (dd, 1H), 6.65 (d, J=3Hz, 1H), 6.72 (d, J=8.6Hz, 2H) and 7.35 (d, J=8.7Hz, 2H); MS m/z 414 (M
+).
Embodiment 107
The preparation of following formula: compound
Steps A: reductive ring closure
Use embodiment 43 preparations 2-thiophene addition product (0.0208g 0.049mmol) for raw material and use generalized method among the embodiment 105 (steps A), improves slightly to it, 0 ℃ to stirring at room after 1 hour 40 minutes, separate crude product.Use the 30%EtOAc/ hexane as eluant, behind the silica gel chromatography purification, obtain red buttery expection product.
1H?NMR?500MHz(CDCl
3)ppm(δ)：1.11(d，18H)，1.24(m，3H)，4.67(d，J＝2.0Hz，1H)，5.50(d，J＝1.8Hz，1H)，6.60-7.12(m，10H)。
Step B: go up the MOM protection
Under 0 ℃, blanket of nitrogen, the dihydrobenzo oxathiin that makes toward top steps A (0.0629g, 0.13mmol) add in the solution in distillatory THF (1mL) mixture of 60%NaH in mineral oil (0.0090g, 0.19mmol).After stopping venting, (0.013mL 0.16mmol) is added drop-wise in the reactant with MOMCl.After 30 minutes, other 1.3 equivalent MOMCl are added in the reactant.In 5 minutes, complete through the TLC monitoring reaction.The gained dark red solution is assigned in EtOAc and the ice/water.Organic layer salt water washing is through dried over sodium sulfate and vacuum concentration.This expection product need not to be further purified and promptly can be used for the next step.
1H?NMR500MHz(CDCl
3)ppm(δ)：1.11(d，18H)，1.24(m，3H)，3.52(s，3H)，4.67(d，J＝2.1Hz，1H)，5.14(m，2H)，5.50(d，J＝1.8Hz，1H)，6.60-7.12(m，10H)。
Step C: desilylation
Use the method for describing among the embodiment 105 (step B),, after use 30%EtOAc/ hexane carries out silica gel chromatography as eluant, obtain the expection product of colorless oil the dihydrobenzo oxathiin desilylation that top step B makes.
1H?NMR?500MHz(CDCl
3)ppm(δ)：3.52(s，3H)，4.69(d，J＝1.8Hz，1H)，5.15(m，2H)，5.51(d，J＝1.8Hz，1H)，6.60-7.15(m，10H)。
Step D:Mitsunobu reaction
According to the method that describes in detail among the embodiment 105 (step C), different is through 4 hours, makes reactant be warmed to room temperature from 0 ℃, carries out silica gel chromatography and (with 30%EtOAc/ hexane eluting, uses 10%MeOH/CH for the second time for the first time
2Cl
2Eluting) after, the material that abovementioned steps is made is converted into the expection product.
1H?NMR?500MHz(CDCl
3)ppm(δ)：1.40-2.60(m，10H)，2.79(t，2H)，3.52(s，3H)，4.10(t，2H)，4.69(d，J＝1.8Hz，1H)，5.15(m，2H)，5.51(d，J＝1.8Hz，1H)，6.60-7.15(m，10H)。
Step e: slough the MOM protection
(0.0401g, 0.080mmol) (0.20mL, 0.40mmol) mixture in MeOH (1.0mL) heated 2.5 hours in 60 ℃ under blanket of nitrogen the material that top step D is made with 2N HCl.Reactant distribution is arrived EtOAc and ice/saturated NaHCO
3In.Organic layer salt water washing is through Na
2SO
4Dry also vacuum concentration.Residue Et
2The O development, the expection product of acquisition white solid.
1H NMR 500MHz (d
6Ppm (δ): the 1.50-3.19 of-acetone+CD3OD) (m, 10H), 3.23 (t, 2H), 4.30 (t, 2H), 5.00 (d, J=1.8Hz, 1H), 5.51 (d, J=1.8Hz, 1H), 6.57-7.25 (m, 10H); MS m/z 454 (M
+).
Embodiment 108
The preparation of following formula: compound
Steps A: reductive ring closure
According to the method for general introduction among the embodiment 44, after 5 hours, the 3-pyridinyl derivatives that 0.0792g embodiment 41 is prepared is converted into its corresponding benzo oxathiin in stirring at room.After using the 30%EtOAc/ hexane to carry out silica gel chromatography the reactant mixture, isolate the expection product as eluant.
1H?NMR?500MHz(CDCl
3)ppm(δ)：1.11(d，18H)，1.24(m，3H)，4.36(d，J＝2.1Hz，1H)，5.05(s，2H)，5.50(d，J＝1.6Hz，1H)，6.77-8.43(m，16H)。
Step B: desilylation
Method according to general introduction among the embodiment 105 (step B), dihydrobenzo oxathiin desilylation with top steps A generation, (for the first time with 50%EtOAc/ hexane eluting, for the second time with 30%EtOAc/ hexane eluting) obtains the expection product behind silica gel chromatography.
1H?NMR500MHz(CDCl
3)ppm(δ)：4.42(d，J＝2.1Hz，1H)，5.07(s，2H)，5.50(d，J＝1.6Hz，1H)，6.77-8.43(m，16H)。
Step C:Mitsunobu reaction
According to the method that describes in detail among the embodiment 105 (step C), different is to make reactant be warmed to room temperature, use 10%MeOH/CH from 0 ℃ through 4 hours
2Cl
2After carrying out silica gel chromatography as eluant, the material that abovementioned steps is made is converted into the expection product.
1H?NMR?500MHz(CDCl
3)ppm(δ)：1.40-2.60(m，10H)，2.80(t，2H)，4.10(t，2H)，4.38(d，J＝1.8Hz，1H)，5.07(s，2H)，5.50(d，J＝1.8Hz，1H)，6.77-8.43(m，16H)。
Step D: debenzylation
The material that step C makes above using is as raw material and use the method for summarizing among the embodiment 105 (step D), uses 10%MeOH/CH
2Cl
2After carrying out silica gel chromatography as eluant, make corresponding cis-3-pyridine radicals dihydrobenzo oxathiin addition product.
1H?NMR?500MHz(CDCl
3)ppm(δ)：1.40-2.60(m，10H)，2.80(t，2H)，4.10(t，2H)，4.36(d，J＝2.1Hz，1H)，5.45(d，J＝1.9Hz，1H)，6.59-8.43(m，11H)；MS?m/z?449(M
+)。
Embodiment 109
The preparation of following formula: compound
Steps A: reductive ring closure
According to the method for general introduction among the embodiment 44, after 30 hours, the 4-pyridinyl derivatives that 0.1871g embodiment 41 is prepared is converted into its corresponding dihydrobenzo oxathiin in stirring at room.After using the 30%EtOAc/ hexane to carry out silica gel chromatography, from reactant mixture, isolate the expection product as eluant.
1H?NMR?500MHz(CDCl
3)ppm(δ)：1.11(d，18H)，1.24(m，3H)，4.32(d，1H)，5.08(s，2H)，5.50(d，1H)，6.60-8.39(m，16H)。
Step B: desilylation
Method according to general introduction among the embodiment 105 (step B), dihydrobenzo oxathiin desilylation with top steps A generation, behind the silica gel chromatography (for the first time with 50%EtOAc/ hexane eluting, for the second time with 30%EtOAc/ hexane eluting), obtain expecting product.
1H?NMR500MHz(CDCl
3)ppm(δ)：4.33(d，1H)，5.07(s，2H)，5.46(d，1H)，6.63-8.37(m，16H)。
Step C:Mitsunobu reaction
According to the method that describes in detail among the embodiment 105 (step C), different is through making reactant be warmed to room temperature from 0 ℃ in 5 hours, and silica gel chromatography (is used 10%MeOH/CH for the first time
2Cl
2Eluting is used 20%EtOAc/CH for the second time
2Cl
2Eluting) after, the material that abovementioned steps is made is converted into the expection product.
1H?NMR?500MHz(CDCl
3)ppm(δ)：1.40-2.60(m，10H)，2.80(t，2H)，4.14(t，2H)，4.32(d，J＝3.0Hz，1H)，5.06(s，2H)，5.49(d，J＝2.1Hz，1H)，6.79-8.38(m，16H)。
Step D: debenzylation
The material that step C makes above using is as raw material and use generalized method among the embodiment 105 (step D), and silica gel chromatography (with 30%EtOAc/ hexane eluting, is used 10%MeOH/CH for the second time for the first time
2Cl
2Eluting) after, obtains the expection product of 4: 1 cis/trans form of mixtures.Cis-isomer:
1H NMR 500MHz (CDCl
3) ppm (δ): 1.40-2.70 (m, 10H), 2.80 (t, 2H), 4.10 (t, 2H), 4.30 (d, J=2.0Hz, 1H), 5.44 (d, J=1.8Hz, 1H), 6.59-8.40 (m, 11H).Transisomer:
1H NMR 500MHz (CDCl
3) ppm (δ): 1.40-2.70 (m, 10H), 2.80 (t, 2H), 4.15 (t, 2H), 4.38 (d, J=8.7Hz, 1H), 4.92 (d, J=8.7Hz, 1H), 6.59-8.46 (m, 11H); MS m/z 449 (M
+).
Embodiment 110
The preparation of following formula: compound
Steps A: reduction
0 ℃ to room temperature, add the sodium borohydride of capacity in the solution of cyclopenta-thioketone in 3mL methanol-dichloromethane (1: 1) that generates in 265.1mg (0.449 mM) embodiment 41 that stirs in batches, so that reduction is fully.Be assigned to this reactant mixture in ethyl acetate/2NHCl/ ice/saline and separate organic facies, use the salt water washing,, filter also evaporation, obtain cyclopenta-mercaptan crude product through anhydrous sodium sulfate drying.This product need not to be further purified and promptly can be used for going on foot down.
Step B: cyclization
At room temperature, crude product and the mixture of 89mg amberlyst 15 in 3mL toluene with steps A preparation above the 266mg (0.449 mM) stirred 2 hours.Remove by filter resin and use the ethyl acetate thorough washing.Evaporated filtrate, gained residue use dichloromethane-hexane (1: 1) as eluant, through the silica gel chromatography purification, obtain trans-dihydrobenzo oxathiin derivant.
1H?NMR?500MHz(CDCl
3)ppm(δ)：1.13(d，18H)，1.26-1.94(m，12H)，3.64(dd，J＝7.8Hz，5.5Hz，1H)，4.78(d，J＝7.8Hz，1H)，5.02(s，2H)，6.6-7.45(m，12H)。
Step C: desilylation
The method of summarizing among the step B according to embodiment 105, the material desilylation with 228.5mg (0.397 mM) abovementioned steps makes obtains corresponding phenol.
Step D:Mitsunobu reaction
According to the method that describes in detail among the embodiment 105 step C, the material that abovementioned steps is made is converted into trans accordingly-cyclopenta-dihydrobenzo oxathiin addition product.
1H?NMR500MHz(CDCl
3)ppm(δ)：1.39-2.0(m，15H)，2.6(m，4H)，2.88(m，2H)，3.66(dd，J＝7.8Hz，5.5Hz，1H)，4.21(m，2H)，4.81(t，J＝7.8Hz，2H)，5.01(s，2H)，6.64-7.49(m，12H)。
Step e: debenzylation
According to the method that describes in detail among the embodiment 105 step D, the material that abovementioned steps is made is converted into trans accordingly-cyclopenta-dihydrobenzo oxathiin product.
1H NMR500MHz (CDCl
3) ppm (δ): 1.29-2.0 (m, 15H), 2.6 (m, 4H), 2.88 (m, 2H), 3.67 (dd, J=8Hz, 5Hz, 1H), 4.18 (m, 2H), 4.77 (t, J=8Hz, 2H), 6.5 (dd, J=2.7Hz, 8.7Hz, 1H), 6.65 (d, 2.7Hz, 1H), 6.77 (d, J=8.7Hz, 1H), 6.88 (d, J=7.5Hz, 2H) and 7.27 (d, J=7.5Hz, 2H).
Embodiment 111
The routine preparation of following formula: compound
Steps A and B: reduction and cyclization
The method of summarizing among the thioketone that use embodiment 39 prepares and steps A that adopts embodiment 110 and the B, preparation following compounds: trans-cyclohexyl derivatives:
1H NMR 500MHz (CDCl
3) ppm (δ): 1.14 (d, 18H), 0.98-1.8 (m, 14H), 3.37 (dd, J=2.5Hz, 8.1Hz, 1H), 5.01 (s, 2H), 5.05 (d, J=8.1Hz, 1H), 6.6-7.44 (m, 12H).Trans-cyclopentyl derivates:
1H NMR 500MHz (CDCl
3) ppm (δ): 1.14 (d, 18H), 1.28-1.9 (m, 12H), 4.53 (m, 1H), 4.93 (d, 1H), 5.01 (s, 2H), 6.6-7.43 (m, 12H).
Step C: desilylation
Trans-dihydrobenzo oxathiin that the use abovementioned steps makes also adopts the method for summarizing among the step B of embodiment 105, preparation following compounds: trans-cyclohexylphenol:
1H NMR 500MHz (CDCl
3) ppm (δ): 1.0-1.8 (m, 11H), 3.3 (m, 1H), 5.05 (s, 2H), 5.1 (d, 1H), 6.6-7.44 (m, 12H).Trans-cyclopenta phenol:
1H NMR 500MHz (CDCl
3) ppm (δ): 1.29-2.0 (m, 9H), 3.55 (dd, J=5.7Hz, 7.6Hz, 1H), 4.95 (d, J=7.6Hz, 1H), 5.02 (s, 2H), 6.6-7.45 (m, 12H).
Step D:Mitsunobu reaction
Trans-dihydrobenzo oxathiin phenol that the use abovementioned steps makes also adopts the method for summarizing among the step C of embodiment 105, preparation following compounds: trans-the cyclohexyl addition product:
1H NMR 500MHz (CDCl
3) ppm (δ): 1.0-1.8 (m, 17H), 2.58 (m, 4H), 2.84 (m, 2H), 3.37 (m, 1H), 4.17 (t, J=6Hz, 2H), 5.0 (s, 2H), 5.08 (d, J=7.8Hz, 1H), 6.6-7.43 (m, 12H).Trans-the cyclopenta addition product:
1H NMR 500MHz (CDCl
3) ppm (δ): 1.29-2.0 (m, 15H), 2.58 (m, 4H), 2.84 (m, 2H), 3.55 (m, 1H), 4.17 (m, 2H), 4.94 (d, J=7.3Hz, 1H), 5.0 (s, 2H), 6.6-7.72 (m, 12H).
Step e: debenzylation
Trans-dihydrobenzo oxathiin addition product that the use abovementioned steps makes also adopts the method for summarizing among the step D of embodiment 105, preparation following compounds: trans-the cyclohexyl addition product:
1H NMR 500MHz (CDCl
3) ppm (δ): 1.0-1.8 (m, 17H), 2.58 (m, 4H), 2.86 (m, 2H), 3.33 (m, 1H), 4.16 (m, 2H), 5.08 (d, J=7.8Hz, 1H), 6.4-7.23 (m, 7H).Trans-the cyclopenta addition product:
1H NMR 500MHz (CDCl
3) ppm (δ): 1.29-2.0 (m, 15H), 2.68 (m, 4H), 2.94 (m, 2H), 3.51 (m, 1H), 4.2 (m, 2H), 4.95 (d, J=7.4Hz, 1H), 6.45-7.31 (m, 7H).
Embodiment 112
The preparation of following formula: compound
Steps A: silylanizing
Under 0 ℃, (0.0395g 0.097mmol) adds 60%NaH (0.0183g, mixture 0.20mmol) in mineral oil to the isopropyl-thioketone that generates in the embodiment 42 that stirs in the solution in distillatory THF (1mL), add then TIPSCl (0.048mL, 0.22mmol).After 35 minutes, the TIPSCl that adds other equivalent is to advance reaction to complete.Reactant distribution is arrived EtOAc and ice/H
2Among the O, organic layer salt water washing through dried over sodium sulfate and vacuum concentration, obtains expecting product.This crude product need not to be further purified and can be used for the next step.
Step B: reduction
Under 0 ℃, blanket of nitrogen, add in the solution of crude product (0.097mmol) in distillatory THF (1mL) that makes toward top steps A the super hydride of 1M THF solution (0.15mL, 0.15mmol).This reactant mixture was stirred 20 minutes, be assigned to EtOAc and ice/H then
2Among the O.Organic layer is further used the salt water washing, through dried over sodium sulfate and vacuum concentration, obtains expecting product.This crude product need not to be further purified and promptly can be used for the next step.
1H?NMR?500MHz(CDCl
3)ppm(δ)：0.90-1.40(m，49H)，1.69(m，1H)，3.10(dd，1H)，4.60(d，1H)，5.05(s，2H)，6.70-7.50(m，12H)。
Step C: desilylation
Under 0 ℃, blanket of nitrogen, add in the solution of material (0.097mmol) in distillatory THF (1mL) that makes toward aforementioned step AcOH (0.018mL, 0.32mmol), add then 1M TBAF THF solution (0.29mL, 0.29mmol).After 15 minutes, reactant distribution is arrived EtOAc and ice/saturated NaHCO
3In.Organic layer salt water washing is through dried over sodium sulfate and vacuum concentration.Use the 40%EtOAc/ hexane as eluant,, obtain yellow foamy expection product through the silica gel chromatography purification.
1H?NMR?500MHz(CDCl
3)ppm(δ)：0.92(d，3H)，0.98(d，3H)，1.59(m，1H)，2.86(dd，1H)，4.62(d，1H)，5.02(q，2H)，6.77-7.45(m，12H)。
Step D: cyclization
Method according to general introduction among the embodiment 110 (step B), after at room temperature stirring 5 hours 15 minutes, material (0.0366g with the abovementioned steps generation, 0.089mmol) be converted into its trans accordingly-dihydrobenzo oxathiin, use the 30%EtOAc/ hexane as eluant, behind the silica gel chromatography purification, obtain the expection product of white solid.
1H?NMR?500MHz(CDCl
3)ppm(δ)：0.98(d，3H)，1.03(d，3H)，1.78(m，1H)，3.57(dd，J＝3.7Hz，J＝8.5Hz，1H)，4.82(d，J＝8.4Hz，1H)，5.02(s，2H)，6.63-7.46(m，12H)。
Step e: Mitsunobu reaction
According to the method that describes in detail among the embodiment 105 (step C), after being warmed to room temperature through 4 hours 20 minutes from 0 ℃, (0.0266g 0.068mmol) is converted into its trans accordingly-isopropyl-dihydrobenzo oxathiin addition product to the material that abovementioned steps is generated.(use 10%MeOH/CH for the first time through the silica gel chromatography purification
2Cl
2Eluting is for the second time with 30%EtOAc/ hexane eluting) after, the expection product of white solid obtained.
1H?NMR?500MHz(CDCl
3)ppm(δ)：0.98(d，3H)，1.02(d，3H)，1.29-1.67(m，6H)，1.78(m，1H)，2.58(m，4H)，2.85(t，2H)，3.57(dd，J＝3.7Hz，J＝8.5Hz，1H)，4.18(t，2H)，4.83(d，J＝8.4Hz，1H)，5.02(s，2H)，6.63-7.46(m，12H)。
Step F: debenzylation
According to the method that describes in detail among the embodiment 105 (step D), (0.0395g 0.068mmol) is converted into its trans accordingly-isopropyl-dihydrobenzo oxathiin product to the material that abovementioned steps is generated.Use 10%MeOH/CH
2Cl
2As eluant, carry out purification by silica gel chromatography.
1H?NMR?500MHz(CDCl
3)ppm(δ)：0.98(d，3H)，1.02(d，3H)，1.29-1.67(m，6H)，1.78(m，1H)，2.58(m，4H)，2.85(t，2H)，3.57(dd，J＝3.7Hz，J＝8.5Hz，1H)，4.18(t，2H)，4.83(d，J＝8.4Hz，1H)，6.48-7.29(m，7H)；MS?m/z?414(M
+)。
Embodiment 113
The preparation of following formula: compound
Steps A: silylanizing
According to the method for general introduction among the embodiment 112 (steps A), with isopropyl-thioketone (0.6314g, 1.5mmol) silylanizing that generates among the embodiment 40.Use the 30%EtOAc/ hexane as eluant,, obtain the expection product of yellow oily through the silica gel chromatography purification.
1H?NMR?500MHz(CDCl
3)ppm(δ)：0.98-1.30(m，49H)，2.35(m，1H)，4.38(d，1H)，4.99(q，2H)，6.33-7.79(m，12H)。
Step B: reduction
According to the method for general introduction among the embodiment 112 (step B), (0.8009g 1.1mmol) is reduced to its alcohol accordingly, and this alcohol need not to be further purified and promptly can be used for the next step with isolating material in the top steps A.
1H?NMR?500MHz(CDCl
3)ppm(δ)：0.98-1.30(m，49H)，1.90(m，1H)，2.92(dd，1H)，4.59(d，1H)，5.05(q，2H)，6.47-7.43(m，12H)。
Step C: desilylation
According to the method for general introduction among the embodiment 112 (step C),, obtain expecting that product, this product need not to be further purified promptly can be used for following step with isolating material (0.022mmol) deprotection among the top step B.
Step D: cyclization
According to the method for general introduction among the embodiment 110 (step B), at room temperature stir 22 hours after, the material that preceding step is generated is converted into its trans accordingly-dihydrobenzo oxathiin.Use the 30%EtOAc/ hexane as eluant,, obtain the expection product of colorless oil through the silica gel chromatography purification.
1H?NMR?500MHz(CDCl
3)ppm(δ)：0.98(d，3H)，1.03(d，3H)，1.79(m，1H)，3.45(dd，1H)，4.98(d，1H)，5.02(s，2H)，6.59-7.46(m，12H)；MS?m/z?393(M
+)。
Step e: Mitsunobu reaction
According to the method that describes in detail among the embodiment 105 (step C), through 6 hours, be warmed to room temperature from 0 ℃ after, (0.008g 0.020mmol) is converted into its trans accordingly-isopropyl-dihydrobenzo oxathiin addition product to the material that preceding step is generated.Use 10%MeOH/CH
2Cl
2As eluant, behind the silica gel chromatography purification, obtain the expection product of yellow oily.
1H?NMR?500MHz(CDCl
3)ppm(δ)：0.98(d，3H)，1.02(d，3H)，1.29-1.67(m，6H)，1.79(m，1H)，2.58(m，4H)，2.81(t，2H)，3.50(dd，J＝3.8Hz，J＝8.3Hz，1H)，4.18(t，2H)，4.97(d，J＝8.2Hz，1H)，5.01(s，2H)，6.59-7.46(m，12H)。
Step F: debenzylation
According to the method that describes in detail among the embodiment 105 (step D), (0.0085g 0.017mmol) is converted into its trans accordingly-isopropyl-dihydrobenzo oxathiin product to the material that preceding step is generated.Use 10%MeOH/CH
2Cl
2As eluant, through the silica gel chromatography purification.
1H?NMR?500MHz(CDCl
3)ppm(δ)：0.98(d，3H)，1.02(d，3H)，1.49-1.70(m，6H)，1.75(m，1H)，2.61(m，4H)，2.85(t，2H)，3.41(dd，J＝3.8Hz，J＝8.3Hz，1H)，4.18(t，2H)，4.96(d，J＝8.2Hz，1H)，6.43-7.26(m，7H)；MS?m/z?414(M
+)。
Embodiment 114
The preparation of following formula: compound
According to the method for general introduction among the embodiment 16, and use 0.36g (2.5 mM) 1,2-diphenyl disulfide phenol (available from Aldrich) uses EtOAc/ hexane (1/5) as eluant, behind silica gel chromatography, obtains the expection product of 221mg (about 20% impurity).
Embodiment 115
The preparation of following formula: compound
Use the method for embodiment 44, carry out the silica gel chromatography purification with the 10%EtOAc/ hexane after, separation (80%) three kind of mixture of products of 121mg (A: B: C=1: 0.1: 0.25).
Embodiment 116
The preparation of following formula: compound
Steps A
Use the method for describing among the embodiment 71 (steps A), with the thia hexadiene ring (thiin) and the coupling of 1-piperidines ethanol of embodiment xx acquisition.Use 3%MeOH/CH
2Cl
2As eluant, behind the silica gel chromatography purification, obtain the expection product of form of mixtures.
Step B
Use the method for describing among the embodiment 71 (step C), the addition product desilylation that steps A is obtained is by HPLC (184.6 * 50.5 microns of Meta Chem Polaris C; Gradient is the 5-75% acetonitrile, reversed-phase column), isolate the expection product A of white solid form:
1H NMR (400MHz, CD
3OD) δ (ppm): 7.2 (m, 2H), 7.1 (m, 2H), 6.9 (m, 2H), 6.8 (m, 4H), 6.55 (d, 2H), 4.75 (m, 2H), 4.3 (m, 2H), 3.6 (br d, 2H), 3.5 (m, 2H), 3.0 (br t, 2H), 1.95 (m, 2H), 1.8 (m, 4H); (MS m/z 464 (M
+).B：
1H?NMR(400MHz，CD
3OD)δ(ppm)：7.4(m，2H)，7.3(m，2H)，7.1(d，2H)，6.95(d，2H)，6.8(d，2H)，6.6(d，2H)，4.3(br?t，2H)，3.6(br?d，2H)，3.5(br?t，2H)，3.05(br?t，2H)，2.0(br?d，2H)，1.8(m，4H)；MS?m/z?462(M
+)。
Assay method
The practicality of The compounds of this invention can be measured by this area those of ordinary skill known method easily.The method that these methods include, but not limited to describe in detail below.
Estrogen receptor is in conjunction with mensuration
Estrogen receptor ligands is designed to use the scintillation proximity assay of tritium for estradiol and recombinant expressed estrogen receptor in conjunction with mensuration.The recombined human ER-α of production total length and ER-β albumen in the bacculoviral expression system.ER-α or ER-β extract dilute with 1: 400 with the phosphate-buffered saline that contains 6mM α-monothioglycerol (monothiolglycerol).The receptor goods of the dilution of every part 200 μ L are added in each hole of 96 hole Flashplate.Culture plate covered with SaranWrap and 4 ℃ of following incubated overnight.
In second day morning, the phosphate buffered saline (PBS) that every part 20 μ l is contained 10% bovine serum albumin is added in each hole of 96 well culture plates, makes it 4 ℃ of insulations 2 hours.Then, culture plate washs with 200 μ l buffer, contains 20mM Tris (pH7.2), 1mMEDTA, 10% glycerol, 50mM KCl and 6mM α-monothioglycerol in this buffer.For in the culture plate of these receptor bag quilts, measuring, add the same buffer of 178 μ l in each hole of 96 well culture plates.In each hole of culture plate, add 20 μ l 10nM then
3H-estradiol solution.
In 0.01nM to 1000nM concentration range inner evaluation test compounds.To test 100 times of stock solutions that prepare test compound with 100%DMSO of required final concentration.The amount of DMSO in the instrument connection of 96 well culture plates should be no more than 1%.Be added to finally that to measure in the culture plate be the test compounds with the 100%DMSO preparation of every part 2 μ l.The sealing culture plate also makes its balance 3 hours at room temperature.In the scintiscan enumerator of installing for counting 96 well culture plates, culture plate is counted.
Ovariectomized rat is analyzed
In OO (OVX) rat is analyzed, with estrogen deficiency cause with the bone resorption that quickens and form relevant porous osteopenia (as, hang down bone density [BMD; Mg/cm
2]).Use BMD and bone resorption/formation result to simulate the variation of the bone that takes place when the women experiences menopause.The analysis of OVX rat is the main body inner analysis pattern of using in the effect aspect the loss of prevention estrogen deficiency bone for the new chemical substance of all main institutes and industrial laboratories research.
The Sprague-Dawley female rats at 6-8 monthly age is implemented ovariectomy, and in 24 hours, begin 42 days treatment with the test compound of carrier or multiple dose.Comprise that untreated vacation-OVX and alendronate-handle (.003mg/kg s.c., q.d.) or 17--processings (.004mg/kg s.c. q.d.) organizes as positive control.But test compound per os, subcutaneous administration maybe can be by the administrations of subcutaneous implantation mini-pump infusion.Before necropsy, use calcein (8mg/kg subcutaneous injection), spy bone fluorescent dye to carry out double labeling in the body.When necropsy, obtain blood, Thigh bone, vertebra fragment and uterus.
The conventional terminal point of OVX rat analysis comprises sclerotin, bone resorption and osteoplastic evaluation.For sclerotin, terminal point is the BMD in the femoral metaphysis of far-end (zone that comprises about 20% cellular bone).Vertebra section (comprising～25% cellular bone) also can be used for BMD and measures.BMD measures x-ray absorptionmetry (DXA, the Hologic 4500A by double energy; Waltham MA) measures.For bone resorption, terminal point is that urine desoxypyridoxine (deoxypyridinoline) is crosslinked, a kind of ossein catabolite (uDPD; Represent with nM DPD/nM creatinine).Use commercial reagent box (Pyrilinks; Metra Biosystems, Mountain View CA) carries out this mensuration.For bone formation, terminal point is that surface and mineral apposition rate, osteoblastic quantity and the active tectology of mineralising measured.This is measured and uses automanual system (Bioquant; R ﹠amp; M Biometrics; Nashville TN), carries out on the proximal tibia metaphysis of the non-decalcificationization of 5 μ m sections.For every kind of terminal point, normal similar terminal point and the determination techniques used in menopausal women.
The rat cholesterol reduces to be analyzed
The Sprague-Dawley rat of the about 250g of counterweight (5 every group) subcutaneous administration is dissolved in the The compounds of this invention in the propylene glycol, administration 4 days.Only give carrier to one group of 5 rat.At the 15th day, with carbon dioxide rat is implemented euthanasia, and obtain blood sample.Analyze the blood plasma cholesterol level of these samples with the cholesterol determination box of buying from Sigma.
MCF-7 estrogen-dependent proliferation assay
MCF-7 cell (ATCC#HTB-22) is people's mammary gland adenocarcinoma cell, its growth needs estrogen.The growth medium of MCF-7 cell (GM) is to replenish the MEM (Minimum Essential Media) (do not contain phenol red) of hyclone (FBS) to 10%.FBS is as estrogenic unique source, and this GM provides the full growth of cell, so be used for the routine growth of cell culture.When the MCF-7 cell being put into wherein the hyclone of handling with 10%Charcoal Dextran (CD-FBS) when substituting in the culture medium of FBS, cell stops differentiation, but still can survive.CD-FBS do not comprise can the survey level estrogen, the culture medium that therefore comprises this serum is called as estrogen and exhausts culture medium (Estrogen Depleted Media (EDM)).Add estradiol in the EDM and stimulate the growth of MCF-7 cell, its EC in dosage dependence mode
50Be 2pM.
The MCF-7 cell of growth is washed for several times with EDM, culture was cultivated minimum 6 days, in EDM to exhaust the endogenous estrogen of cell.Then the 0th day when beginning (analyze), the cell that these estrogen are exhausted is added in 96 well culture plates with the density of 1000 cells/well in EDM, and adding volume is 180 μ l/ holes.At the 1st day,, obtain the test compound of dilution in further 1: 10 with being added in the 180 μ l culture medium in the suitable hole of Tissue Culture Plate with 10 times of serial dilution test compounds and with these diluents of 20 μ l among the EDM.At the 4th and 7 day that analyzes, culture is supplied gas and replaced with as above fresh EDM and test compound.When suitable contrast reaches the fusion rate of 80-90%, finished to analyze at 8-10 days.At this moment, culture supernatants is supplied gas cell PBS washed twice, solution that washing is supplied gas and the protein content of measuring every hole.Estimate every kind of drug dilution liquid with minimum 5 holes, the dilution range of every kind of test compound is 0.001nM-1000nM in analysis.Use the probability of above-mentioned analytical method determination test chemical compound as the estradiol agonist.
Be the antagonist activities of evaluation test chemical compound, the MCF-7 cell was kept 6 days at EDM at least.Then the 0th day when beginning (analyze), the cell that these estrogen are exhausted is added in the 96 porocyte culture plates with the density of 1000 cells/well in EDM, and adding volume is 180 μ l/ holes.First day, the test compound that will comprise in the fresh culture of 3pM estradiol was added in the cell.At the 4th and 7 day that analyzes, culture supernatant is supplied gas and replaced with the fresh EDM that contains 3pM estradiol and test compound.When suitable contrast reaches the fusion rate of 80-90%, finished to analyze the protein content of also as above measuring in each hole at 8-10 days.
Rat endometrium dystopy modelAnimal: kind: Rattus norvegicus kind system: Sprague-Dawley CD supplier: Charles River Laboratories, Raleigh, the NC sex: female, body weight: 200-240 gram
Be housed in rat in the Merlon cage separately and give Teklad Global Diet 2016 (Madison WI) and the bottled inverse osmosis purified water of freely drinking, makes it keep 12/12 bright/dark circulation.
Rat is used Telazol
TM(20mg/kg, ip) and oxymorphone (0.2mg/kg, sc) anesthesia and its back of the body abdomen one side is placed on the aseptic coverlet.Use is placed on following recirculated water blanket and keeps body temperature.Operative site is shaved clean povidone-iodine/isopropyl alcohol or Duraprep (3M) cleaning three times of also using with shear.Cut sides covers with aseptic list.
Use aseptic technique, see through skin, subcutaneous and Musclar layer, make 5cm center line hypogastric region otch.Implement bilateral oophorectomy.Ligation left side uterine vascular also excises the left side cornua uteri of one section 7mm.With 4-0 catgut suture uterus.From endometrium aseptic separating uterus flesh layer and be trimmed to 5 * 5mm.The endometrium of pruning is implanted the veutro peritoneal wall of the epithelial cell internal layer section relative with peritoneal wall.Use aseptic 6-0 silk thread that the endometrial tissue of transplanting is sewn onto on the health wall at its place, four angles.Contain chromic catgut with aseptic 4-0 and sew up the abdominal muscles layer.With aseptic rustless steel surgery forceps sealing skin incision.Estrogen ball (Innovative Research of America, 0.72ng/ ball at 90 days aseptic slow release of the subcutaneous implantation of omoplate dorsal part location; Circulation estrogen is equivalent to 200-250pg/mL).The aseptic implantable sequencing temperature transponder (IPTT) of subcutaneous injection in omoplate dorsal part zone (BMDS, Seaford, DE).Observe these rats, until can walking fully, and make their from calm 3 weeks of rehabilitation of operation.
Three weeks behind the implantation endometrial tissue, adopt the sterilization surgical operation to prepare and technology, animal is carried out multiple laparotomy ventrotomy.Estimate the graft acceptability of transplanting and measure this zone and record with caliper.From research, remove the animal that repels graft.With the animal grouping, so that every group of average graft volume that generation is similar.
Begin one day after to handle in the laparotomy ventrotomy second time, handled continuously 14 days with medicine or excipient (contrast).10 uses in morning BMDS scanning device writes down body temperature every other day.
When processing in 14 days finishes, animal is implemented euthanasia with excess carbon dioxide.By the cardiocentesis blood sampling, be used to measure the circulation estrogen level.Open abdominal part, check, measure, downcut graft and write down weight in wet base.Excision right side cornua uteri also writes down weight in wet base and dry weight.
Pharmaceutical composition
As specific embodiments of the present invention, the chemical compound of 25mg embodiment 71 with pulverizing to such an extent that enough thin lactose is prepared, is obtained the mixture that total amount is 580-590mg, fill it in No. 0 hard gelatin capsule.
Claims (20)
1. the chemical compound of following formula and officinal salt thereof:
Wherein
R
1, R
2, R
3And R
4Be selected from hydrogen, C independently of one another
1-5Alkyl, C
3-8Cycloalkyl, C
2-5Alkenyl, C
2-5Alkynyl, C
3-8Cycloalkenyl group, phenyl, heteroaryl, heterocyclic radical, CF
3, OR
6, halogen, C
1-5Alkylthio group, thiocyanogen, cyano group ,-CO
2H ,-COOC
1-5Alkyl ,-COC
1-5Alkyl ,-CONZ
2,-SO
2NZ
2With-SO
2C
1-5Alkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, phenyl, heteroaryl, heterocyclic radical can randomly be replaced by following group: C
1-5Alkyl, C
3-8Cycloalkyl, CF
3, phenyl, heteroaryl, heterocyclic radical ,-OR
6, halogen, amino, C
1-5Alkylthio group, thiocyanogen, cyano group ,-CO
2H ,-COOC
1-5Alkyl ,-COC
1-5Alkyl ,-CONZ
2,-SO
2NZ
2With-SO
2C
1-5Alkyl;
R
5Be selected from C
1-5Alkyl, C
3-8Cycloalkyl, C
2-5Alkenyl, C
2-5Alkynyl, C
3-8Cycloalkenyl group, phenyl, heteroaryl, heterocyclic radical, wherein said group can randomly be replaced by following groups: C
1-5Alkyl, C
3-8Cycloalkyl, CF
3, phenyl, heteroaryl, heterocyclic radical ,-OR
6, halogen, amino, C
1-5Alkylthio group, thiocyanogen, cyano group ,-CO
2H ,-COOC
1-5Alkyl ,-COC
1-5Alkyl ,-CONZ
2,-SO
2NZ
2With-SO
2C
1-5Alkyl;
X and Y are selected from oxygen, sulfur, sulfoxide and sulfone independently of one another;
R
6Be selected from hydrogen, C
1-5Alkyl, benzyl, methoxy, three Organosilyls, C
1-5Alkyl-carbonyl, alkoxy carbonyl group and CONZ
2
Each Z is independently selected from hydrogen, C
1-5Alkyl, trifluoromethyl, wherein said alkyl can randomly be replaced by following groups: C
1-5Alkyl, CF
3,-OR
6, halogen, amino, C
1-5Alkylthio group, thiocyanogen, cyano group ,-CO
2H ,-COOC
1-5Alkyl ,-COC
1-5Alkyl, CONV
2,-SO
2NV
2With-SO
2C
1-5Alkyl;
Perhaps the nitrogen that is connected with them of two Z can form 3-8 unit ring together, described ring can randomly comprise the atom that is selected from carbon, oxygen, sulfur and nitrogen, wherein said ring can be saturated or unsaturated, and the carbon atom of described ring can randomly be selected from following substituent group replacement: C by one to three
1-5Alkyl, CF
3,-OR
6, halogen, amino, C
1-5Alkylthio group, thiocyanogen, cyano group ,-CO
2H ,-COOC
1-5Alkyl ,-COC
1-5Alkyl ,-CONV
2,-SO
2NV
2With-SO
2C
1-5Alkyl;
Each V is independently selected from C
1-5Alkyl, CF
3,-OR
6, halogen, amino, C
1-5Alkylthio group, thiocyanogen, cyano group ,-CO
2H ,-COOC
1-5Alkyl ,-COC
1-5Alkyl and-SO
2C
1-5Alkyl;
Each n is the integer of 0-5 independently.
2. the chemical compound of claim 1 and officinal salt thereof, wherein Y is that sulfur and X are oxygen.
3. the chemical compound of claim 2 and officinal salt thereof, wherein
R
1, R
2, R
3And R
4Be selected from hydrogen, C independently of one another
1-5Alkyl, C
3-8Cycloalkyl, C
2-5Alkenyl, C
2-5Alkynyl ,-OR
6And halogen, condition is R
2And R
3In one be-OH;
R
5Be selected from C
3-8Cycloalkyl, phenyl, heteroaryl and heterocyclic radical, wherein said group can be randomly by-OR
6Replace with halogen;
R
6Be selected from hydrogen, C
1-5Alkyl, benzyl, methoxy and triisopropyl silicyl.
4. the chemical compound of claim 3 is selected from following compounds and their officinal salt:
5. the chemical compound of claim 3 and officinal salt thereof,
Wherein
R
1, R
2, R
3And R
4Be selected from hydrogen, C independently of one another
1-5Alkyl, C
3-8Cycloalkyl, C
2-5Alkenyl, C
2-5Alkynyl ,-OR
6And halogen, condition is R
2And R
3In one be-OH; R
6Be selected from hydrogen, C
1-5Alkyl, benzyl, methoxy and triisopropyl silicyl;
R
7Be selected from hydrogen, C
1-5Alkyl, halogen, trifluoromethyl and-OR
6
Each Z is independently selected from hydrogen, C
1-5Alkyl, trifluoromethyl, wherein said alkyl can randomly be replaced by following groups: C
1-5Alkyl, CF
3,-OR
6, halogen, amino, C
1-5Alkylthio group, thiocyanogen, cyano group ,-CO
2H ,-COOC
1-5Alkyl ,-COC
1-5Alkyl, CONV
2,-SO
2NV
2With-SO
2C
1-5Alkyl;
Perhaps the nitrogen that is connected with them of two Z can form 3-8 unit ring together, described ring can randomly comprise the atom that is selected from carbon, oxygen, sulfur and nitrogen, wherein said ring can be saturated or unsaturated, and the carbon atom of described ring can randomly be selected from following substituent group replacement: C by one to three
1-5Alkyl, CF
3,-OR
6, halogen, amino, C
1-5Alkylthio group, thiocyanogen, cyano group ,-CO
2H ,-COOC
1-5Alkyl ,-COC
1-5Alkyl ,-CONV
2,-SO
2NV
2With-SO
2C
1-5Alkyl;
Each V is independently selected from C
1-5Alkyl, CF
3,-OR
6, halogen, amino, C
1-5Alkylthio group, thiocyanogen, cyano group ,-CO
2H ,-COOC
1-5Alkyl ,-COC
1-5Alkyl and-SO
2C
1-5Alkyl;
Each n is the integer of 0-5 independently;
Each m is the integer of 0-4 independently.
6. the chemical compound of claim 5 is selected from following compounds and officinal salt thereof:
7. the chemical compound of claim 5 is the chemical compound and the officinal salt thereof of following formula:
Wherein
R
1, R
2, R
3And R
4Be selected from hydrogen, C independently of one another
1-5Alkyl, C
3-8Cycloalkyl, C
2-5Alkenyl, C
2-5Alkynyl ,-OR
6And halogen, condition is R
2And R
3In one be-OH;
R
6Be selected from hydrogen, C
1-5Alkyl, benzyl, methoxy and triisopropyl silicyl;
R
7Be selected from hydrogen, C
1-5Alkyl, halogen, trifluoromethyl and-OR
6
R
8Be independently selected from hydrogen, C
1-5Alkyl, CF
3,-OR
6, halogen, amino, C
1-5Alkylthio group, thiocyanogen, cyano group ,-CO
2H ,-COOC
1-5Alkyl ,-COC
1-5Alkyl ,-CONV
2,-SO
2NV
2With-SO
2C
1-5Alkyl;
Each V is independently selected from C
1-5Alkyl, CF
3,-OR
6, halogen, amino, C
1-5Alkylthio group, thiocyanogen, cyano group ,-CO
2H ,-COOC
1-5Alkyl ,-COC
1-5Alkyl and-SO
2C
1-5Alkyl;
Each m is the integer of 0-4 independently;
Each p is the integer of 0-4 independently.
8. the chemical compound of claim 7 is selected from following compounds and officinal salt thereof:
9. the chemical compound of claim 5 is following formula: compound and officinal salt thereof:
Wherein
R
1, R
2, R
3And R
4Be selected from hydrogen, C independently of one another
1-5Alkyl ,-OR
6And halogen, condition is R
2And R
3In one be-OH;
R
6Be selected from hydrogen, C
1-5Alkyl, benzyl, methoxy and triisopropyl silicyl;
R
7Be selected from hydrogen, C
1-5Alkyl, halogen, trifluoromethyl and-OR
6
Each m is 1 or 2 integer independently.
10. the chemical compound of claim 9 is selected from following compounds and officinal salt thereof:
11. the chemical compound of claim 1 and officinal salt thereof, wherein X is that sulfur and Y are sulfur.
12. the chemical compound of claim 11 is selected from following compounds and officinal salt thereof:
13. a pharmaceutical composition comprises chemical compound and pharmaceutically suitable carrier of claim 1.
14. combine the pharmaceutical composition of preparation with pharmaceutically suitable carrier by chemical compound with claim 1.
15. the method for a pharmaceutical compositions comprises that the chemical compound with claim 1 combines with pharmaceutically suitable carrier.
16. a method that produces the estrogen receptor regulating action in the mammal that needs the estrogen receptor regulating action comprises the chemical compound to the claim 1 of administration treatment effective dose.
17. the method for claim 16, wherein the estrogen receptor regulating action is the estrogen receptor agonism effect.
18. the method for claim 17, wherein the estrogen receptor agonism effect is an ER α receptor agonism.
19. a treatment or the method for preventing women's postmenopausal osteoporosis, this method comprises the chemical compound to the claim 1 of women's administering therapeutic effective dose of this treatment of need or prevention.
20. method for the treatment of or preventing the following disease of women, this method comprises that described disease is estrogen-dependent breast carcinoma, hysteromyoma, restenosis, endometriosis and hyperlipemia to the chemical compound of the claim 1 of women's administering therapeutic effective dose of this treatment of need.
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|---|---|---|---|
| US24158200P | 2000-10-19 | 2000-10-19 | |
| US60/241,582 | 2000-10-19 |
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|---|---|
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| JP (1) | JP2004511502A (en) |
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| US20030225132A1 (en) * | 2002-04-11 | 2003-12-04 | Dininno Frank P. | Estrogen receptor modulators |
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| HRP20040906B1 (en) | 2002-05-10 | 2013-01-31 | Hoffmann La Roche | Bisphosphonic acid for the treatment and prevention of ostreoporosis |
| AU2003292625B2 (en) * | 2002-12-26 | 2008-07-24 | Eisai R & D Management Co., Ltd. | Selective estrogen receptor modulators |
| EP1909788A2 (en) | 2005-07-29 | 2008-04-16 | Resverlogix Corp. | Pharmaceutical compositions for the prevention and treatment of complex diseases and their delivery by insertable medical devices |
| EP1944301A4 (en) * | 2005-10-27 | 2012-01-04 | Msd Kk | NEW BENZOXATHINE DERIVATIVE |
| WO2008092231A1 (en) | 2007-02-01 | 2008-08-07 | Resverlogix Corp. | Compounds for the prevention and treatment of cardiovascular diseases |
| EP2382194B1 (en) | 2009-01-08 | 2014-03-12 | Resverlogix Corp. | Compounds for the prevention and treatment of cardiovascular disease |
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| TR201818390T4 (en) | 2009-04-22 | 2019-01-21 | Resverlogix Corp | NEW ANTI-INFLAMMATORY AGENTS |
| US8703810B2 (en) | 2010-06-10 | 2014-04-22 | Seragon Pharmaceuticals, Inc. | Estrogen receptor modulators and uses thereof |
| WO2011159769A2 (en) | 2010-06-17 | 2011-12-22 | Aragon Pharmaceuticals, Inc. | Indane estrogen receptor modulators and uses thereof |
| WO2013064900A1 (en) | 2011-11-01 | 2013-05-10 | Resverlogix Corp. | Oral immediate release formulations for substituted quinazolinones |
| SG11201403002RA (en) | 2011-12-14 | 2014-07-30 | Seragon Pharmaceuticals Inc | Fluorinated estrogen receptor modulators and uses thereof |
| US9073878B2 (en) | 2012-11-21 | 2015-07-07 | Zenith Epigenetics Corp. | Cyclic amines as bromodomain inhibitors |
| WO2014080291A2 (en) | 2012-11-21 | 2014-05-30 | Rvx Therapeutics Inc. | Biaryl derivatives as bromodomain inhibitors |
| CA2895905A1 (en) | 2012-12-21 | 2014-06-26 | Zenith Epigenetics Corp. | Novel heterocyclic compounds as bromodomain inhibitors |
| WO2016147053A1 (en) | 2015-03-13 | 2016-09-22 | Resverlogix Corp. | Compositions and therapeutic methods for the treatment of complement-associated diseases |
-
2001
- 2001-10-15 AU AU2002232381A patent/AU2002232381B2/en not_active Ceased
- 2001-10-15 PL PL01361053A patent/PL361053A1/en not_active Application Discontinuation
- 2001-10-15 MX MXPA03003485A patent/MXPA03003485A/en unknown
- 2001-10-15 KR KR10-2003-7005518A patent/KR20030042020A/en not_active Withdrawn
- 2001-10-15 BR BR0114689-0A patent/BR0114689A/en not_active Application Discontinuation
- 2001-10-15 EE EEP200300153A patent/EE200300153A/en unknown
- 2001-10-15 EA EA200300474A patent/EA200300474A1/en unknown
- 2001-10-15 CA CA002424729A patent/CA2424729A1/en not_active Abandoned
- 2001-10-15 IL IL15498401A patent/IL154984A0/en unknown
- 2001-10-15 AU AU3238102A patent/AU3238102A/en active Pending
- 2001-10-15 WO PCT/US2001/042735 patent/WO2002032377A2/en not_active Application Discontinuation
- 2001-10-15 EP EP01987654A patent/EP1333827A2/en not_active Withdrawn
- 2001-10-15 HU HU0303563A patent/HUP0303563A2/en unknown
- 2001-10-15 JP JP2002535616A patent/JP2004511502A/en not_active Withdrawn
- 2001-10-15 SK SK477-2003A patent/SK4772003A3/en unknown
- 2001-10-15 CN CNA018176720A patent/CN1469743A/en active Pending
-
2002
- 2002-04-15 PE PE2002000308A patent/PE20021083A1/en not_active Application Discontinuation
-
2003
- 2003-03-26 BG BG107676A patent/BG107676A/en unknown
- 2003-03-27 IS IS6761A patent/IS6761A/en unknown
- 2003-04-15 NO NO20031737A patent/NO20031737L/en unknown
- 2003-04-17 EC EC2003004558A patent/ECSP034558A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NO20031737L (en) | 2003-06-19 |
| BR0114689A (en) | 2003-07-01 |
| KR20030042020A (en) | 2003-05-27 |
| PE20021083A1 (en) | 2002-12-16 |
| WO2002032377A2 (en) | 2002-04-25 |
| HUP0303563A2 (en) | 2004-03-01 |
| WO2002032377A3 (en) | 2002-08-22 |
| EE200300153A (en) | 2003-06-16 |
| NO20031737D0 (en) | 2003-04-15 |
| JP2004511502A (en) | 2004-04-15 |
| EP1333827A2 (en) | 2003-08-13 |
| EA200300474A1 (en) | 2003-10-30 |
| AU3238102A (en) | 2002-04-29 |
| ECSP034558A (en) | 2003-06-25 |
| IL154984A0 (en) | 2003-10-31 |
| BG107676A (en) | 2003-11-28 |
| SK4772003A3 (en) | 2003-08-05 |
| CA2424729A1 (en) | 2002-04-25 |
| PL361053A1 (en) | 2004-09-20 |
| MXPA03003485A (en) | 2003-07-14 |
| IS6761A (en) | 2003-03-27 |
| AU2002232381B2 (en) | 2004-11-18 |
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