CN1548434B - Benzothiophene compounds and their preparation and medicine use - Google Patents
Benzothiophene compounds and their preparation and medicine use Download PDFInfo
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Abstract
The present invention discloses one kind of benzothiophene compounds and their preparation process and medicine use. The present invention also discloses their physiologically acceptable salts, their preparation and the application in preparing medicine for preventing and treating women's post-menopause syndromes.
Description
Technical field
The present invention relates to benzothiophene derivative and salt thereof is the new compound that purpose is developed with prevention and treatment women's post-menopause syndrome.
Background technology
Women's post-menopause syndrome mainly shows: osteoporosis, estrogen-dependent type cancer (mammary cancer, uterus carcinoma and ovarian cancer), cardiovascular disorder, senile dementia etc.
Osteoporosis is postmenopausal women's common disease and a frequently-occurring disease.Chinese women's sickness rate more than 60 years old is about 40%.Most of women 3-6 after menelipsis can lose the 20%-60% of bone amount.In post-menopausal osteoporosis, the clean absorption of girder sclerotin and losing can cause fracture.Thereby vertebra, femur, forearm equal altitudes rely on the easiest fracture the in position of girder support.The fracture of elderly woman is mainly vertebra comminuted fracture (47%), hip fracture (20%), wrist fracture (13%), and the 20%-30% of its mortality ratio is relevant with hip fracture.Though modal controversies in hormone replacement in the elderly can relief of symptoms, and significant side effects is arranged: mainly be that oestrogenic hormon stimulates endometrial hyperplasia, cause cyclic hemorrhage sometimes, even may bring out carcinoma of endometrium and mammary cancer.Bis-phosphonic acids has serious gastrointestinal reaction, and the consequence of long term and unclear.Raloxifene (Raloxifene) is that first is approved for the osteoporotic selective estrogen receptor modulators of treatment, but the tendency that increases hectic fever and uterine hemorrhage is arranged.
Mammary cancer is another common disease of elderly woman, and main chemotherapy is to use estrogen antagonist at present, and tamoxifen (Tamoxifen) in the highest flight.But tamoxifen also has very big shortcoming.It shows the character of estrogen agonist in the uterus, the cancer cells in uterus is had hormesis.
Cardiovascular disorder is another main illness of post-menopause syndrome.Postmenopausal women's blood lipid level of accepting controversies in hormone replacement in the elderly can obviously reduce, but a lot of women can not tolerate the side effect of controversies in hormone replacement in the elderly.
Other disease relevant with oestrogenic hormon also has endometriosis, uterus fiber disease.
To be uterine endometrium produce abnormal response and dystopy growth in unsuitable tissue to normal hormone control to the endometriotic cause of disease, starts local inflammation, this disease have an intense pain hemorrhage with uterine endometrium or peritoneal cavity often, in often cause sterile.The main therapy of this disease is continuous low dosage hormonotherapy.Oestrogenic hormon low dosage treatment continuously has the danger that causes carcinoma of endometrium, and progestogen low dosage treatment continuously can be induced amenorrhoea, and the uterine endometrium growth is degenerated, and tool is sterile to causing.The male sex hormone treatment has serious manlike effect.
Fibrosis of uterus comprises metrauxe, hysteromyoma, fibrosis of uterus, fibrosis metritis etc., generally adopts operative treatment.So need to propose the new therapy of fibrosis of uterus.
In sum, these diseases relevant with oestrogenic hormon all need medicine evident in efficacy, safer.Selective estrogen receptor modulators (Selective Estrogen Receptor Modulators) optionally presents excitement or antagonistic action according to target tissue with the different of hormone environment, thereby is the medicine of more satisfactory treatment women's post-menopause syndrome.The raloxifene that has gone on the market (Raloxifene hydrochloride, the patent No.: the A Zuo former times sweet smell (Arzoxifenehydrochloride that US4418068) and just carries out phase iii clinical trial, patent No. EP0729956A1) can effectively prevent and treat women's osteosporosis after menopause disease and mammary cancer etc., but these two kinds of medicines all there is the dangerous tendency that increases degree of depth venous thrombosis.
Summary of the invention
The object of the invention provides a class benzothienyl compounds to be estrogenic agents, and they and estrogen receptor have good affinity, can promote bone forming, and good effect, and side effect is little, has the syndromes that produces behind prevention and the treatment postmenopausal women.
Another object of the present invention is the preparation method who discloses this compounds.
General formula I is represented benzothiophenes of the present invention.
Or formula I physiologically acceptable salt,
R wherein
1=R
2=OH, Y=-C=O, X=N,
R
3Be H, HC (CH
3)
2, 4-chloro-benzyl ,-chlorobenzene formacyl, right-chlorobenzene formacyl ,-methyl benzoyl, to nitrobenzyl, the 4-methylsulfonyl, the 4-p-toluenesulfonyl, the 4-sulfanilyl radical, the 2-furancarbonyl, pyridine-4-formyl radical, or 4,6-dimethyl pyrimidine-2-base.
The abbreviation that is used to describe general formula I has as giving a definition:
OH representation hydroxy, Y are that to represent Y be carbonyl to C=O.
Can make medicinal salt and represent the salt that the tertiary amine part is become with mineral acid or organic acid in the general formula molecule.
According to the present invention, preferred formula I compound is: R
1=R
2=OH, Y=C=O, X=N, R
3=HC (CH
3)
2, and hydrochloride.
According to the present invention, preferred formula I compound is: R
1=R
2=OH, Y=C=O, X=N, R
3=4-chloro-benzyl, and hydrochloride.
According to the present invention, preferred formula I compound is: R
1=R
2=OH, Y=C=O, X=N, R
3=-chlorobenzene formacyl, and hydrochloride.
According to the present invention, preferred formula I compound is: R
1=R
2=OH, Y=C=O, X=N, R
3=right-chlorobenzene formacyl, and hydrochloride.
According to the present invention, preferred formula I compound is: R
1=R
2=OH, Y=C=O, X=N, R
3=-methyl benzoyl, and hydrochloride.
According to the present invention, preferred formula I compound is: R
1=R
2=OH, Y=C=O, X=N, R
3=right-nitrobenzyl, and hydrochloride.
According to the present invention, specifically be preferably as follows the formula compound:
2-(4-hydroxy phenyl)-3-[4-(4-sec.-propyl piperazine)-benzoyl]-6-hydroxyl-thionaphthene;
2-(4-hydroxy phenyl)-3-[4-(4-benzyl chloride base piperazine)-benzoyl]-6-hydroxyl-thionaphthene;
2-(4-hydroxy phenyl)-3-{4-[4-(3-chlorobenzene formacyl piperazine)]-benzoyl }-6-hydroxyl-thionaphthene;
2-(4-hydroxy phenyl)-3-{4-[4-(4-chlorobenzene formacyl piperazine)]-benzoyl }-6-hydroxyl-thionaphthene;
2-(4-hydroxy phenyl)-3-{4-[4-(3-methyl benzoyl piperazine)]-benzoyl }-6-hydroxyl-thionaphthene;
2-(4-hydroxy phenyl)-3-[4-(4-is to nitrobenzyl-piperazine)-benzoyl]-6-hydroxyl-thionaphthene.
The benzothiophenes that the present invention relates to formula I is implemented as follows
It is described to press US4133814, at first react the formation intermediate A with the meta-methoxy thiophenol and to methoxyl group-ω-bromoacetophenone in ethanolic soln in the presence of potassium hydroxide, A under polyphosphoric acid (PPA) effect cyclization takes place and simultaneous isomerization becomes intermediate B.Intermediate B is in the presence of Lewis acid such as aluminum trichloride (anhydrous) and to the halogen Benzoyl chloride, for example: to fluorobenzoyl chloride or parabromobenzoyl chloride, reaction obtains intermediate C.C and the reaction of excessive Piperazine anhydrous, compd E, simultaneously, C also can be earlier and benzyl diethylenediamine react, catalytic hydrogenolysis is sloughed benzyl and must the E compound then.This E compound again with R
3Active group such as carboxylic acid halides, acid anhydrides, halides, sulphonate reaction, under aluminum chloride/sulfur alcohol or boron tribromide effect, slough protecting group then and obtain target product.
Above-mentioned benzothiophenes carries out following pharmacological testing:
The oestrogenic hormon nuclear receptor is in conjunction with experiment
The compound concentration gradient is all diluted with DMSO.Experiment is carried out in 96 orifice plates, add in every hole Assaybuffer (by ER binding buffer, ER α or ER β, [
3H] 17 β-estradiol is formulated) test compound behind 225 μ L and the 25 μ L flaps, the vibration mixing was hatched 12 hours at 4 ℃.Every then hole adds 200 μ L6.25%HA mixed solutions, and the vibration mixing was hatched 10 minutes for 4 ℃.With the centrifugal termination reaction of mixture (2500rpm, 3-5 minute), supernatant discarded adds scintillation solution, measures with Wallac MicroBeta Trilux 1450-023 liquid scintillation instrument.This test has repeated three times.
External nuclear receptor competitive binding experiment result is as follows:
| R 3(X＝N) | Compound | IC50(α，nM) | Ki(α) | IC50(β，nM) | Ki(β) |
| Raloxifene | 0.73 | 0.63 | 18.90 | 17.94 | |
| -CH 2C 6H 5 | Y-78 | 0.97 | 0.83 | 5.53 | 5.25 |
| -COC 6H 5 | Y-80 | 0.86 | 0.74 | 25.29 | 24.01 |
| O O | Y-84 | 2.65 | 2.29 | 20.09 | 19.07 |
| X＝O | Y-88 | 8.00 | 6.90 | 72.62 | 68.94 |
| p-CH 3C 6H 5CO- | Y-97 | 2.74 | 2.37 | 4.94 | 4.69 |
| m-Cl-C 6H 5CO | Y-100 | 0.46 | 0.39 | 3.70 | 3.52 |
| p-Cl-C 6H 5CO | Y-101 | 0.78 | 0.67 | 4.02 | 3.82 |
| m-OH-C 6H 5CO | Y-102 | 1.39 | 1.20 | 19.77 | 18.76 |
| o-OH-C 6H 5CO | Y-105 | 3.05 | 2.63 | 7.92 | 7.52 |
| o-CH 3C 6H 5CO | Y-106 | 3.94 | 3.40 | 17.67 | 16.78 |
| m-CH 3C 6H 5CO | Y-107 | 0.27 | 0.23 | 12.47 | 11.84 |
| o-Cl-C 6H 5CO | Y-110 | 1.72 | 1.49 | 3.21 | 3.04 |
| O N | Y-113 | 14.46 | 12.46 | 93.57 | 88.83 |
| O N | Y-116 | 523392.19 | 451200.17 | 8940287.01 | 8487614.25 |
| p-NO 2-C 6H 5CO | Y-118 | 2.15 | 1.85 | 1.27 | 1.21 |
| p-Cl-C 6H 5CH 2 | Y-119 | 0.22 | 0.19 | 9.07 | 8.61 |
| o-NO 2-C 6H 5CO | Y-120 | 3.58 | 3.09 | 12.90 | 12.25 |
| p-NO 2-C 6H 5CH 2 | Y-123 | 0.43 | 0.38 | 14.22 | 13.50 |
| (CH 3) 2CH- | Y-134 | 0.28 | 0.25 | 33.92 | 32.20 |
| Y-137 | 1.08 | 0.96 | 18.15 | 17.23 | |
| CH 3 N H 3C N | Y-140 | 2.12 | 1.88 | 66.52 | 63.15 |
| -CH 2CH 2CH 3 | Y-149 | 1.43 | 1.27 | 29.37 | 27.89 |
Selective estrogen receptor is regulated active control women's post-menopause syndrome, comprises postmenopausal osteoporosis, the cardiovascular disorder relevant with hyperlipidemia, the tumour that oestrogenic hormon is relevant: comprise mammary cancer, uterus carcinoma and ovarian cancer.The selective estrogen receptor activity of compound of Formula I also is used to prevent and treat the gynaecopathia relevant with oestrogenic hormon, as fibrosis of uterus disease, endometriosis.
Term used herein " women's post-menopause syndrome " refers to post-menopausal osteoporosis, the cardiovascular disorder that hyperlipidemia is relevant, tumour, especially mammary cancer, uterus carcinoma and ovarian cancer that oestrogenic hormon is relevant; Term " disease relevant with oestrogenic hormon " is meant women's fibrosis of uterus disease, endometriosis.
Embodiment
Below in conjunction with embodiment the present invention is done detailed elaboration, but do not limit the present invention.
Embodiment 1 6-methoxyl group-2-(4-p-methoxy-phenyl)-3-(4-fluoro-benzoyl)-thionaphthene-(Y-69)
In 1.0 gram 4-fluorobenzoic acids (7.14mmol), add 6ml, the SOCl that heavily steamed
2.1 dripping DME refluxed 1 hour.Steam and remove the chlorination sulfoxide, drain as far as possible with water pump.Add 30mL drying 1 subsequently therein, 2-ethylene dichloride, 2-(4-the p-methoxy-phenyl)-6-methoxyl group-thionaphthene (7.03mmol) of 1.9 grams, 3.8 gram aluminum trichloride (anhydrous)s (28.5mmol).Spend the night 20mLTHF quencher reaction 5 ℃～10 ℃ reactions.Dichloromethane extraction merges organic phase, anhydrous sodium sulfate drying.Steaming desolventizes back silica gel column chromatography (petrol ether/ethyl acetate 15/1) and obtains yellow powder 2.4 grams, two step yields 86%.NMR(400MHz，CDCl
3)δ3.74(3H，s)3.89(3H，s)6.74(2H，q，J＝6.8)6.94(2H，t，J＝9.0，J＝8.4)7.0(1H，dd，J＝9.0，J＝2.4)7.29(2H，q，J＝6.8)7.32(1H，d，J＝2.4)7.63(1H，d，J＝9.0)7.78(2H，m)。
Embodiment 2 6-methoxyl group-2-(4-p-methoxy-phenyl)-3-[4-(4-benzyl diethylenediamine-)-1-benzoyl]-thionaphthene (Y-66)
Dissolving 2.5 gram Y-69 in exsiccant 10mL N-Methyl pyrrolidone, the 1.8mL benzyl diethylenediamine, the 3mL triethylamine, reaction is 20 hours under 110 ℃ of oil baths, pours in the water ethyl acetate extraction, anhydrous sodium sulfate drying into.Steaming desolventizes back silica gel column chromatography (petrol ether/ethyl acetate 2/1) and obtains 3.08 gram yellow crystals, yield 88%.NMR(400MHz，CDCl
3)δ2.58(4H，s)3.33(4H，s)3.58(2H，s)3.75(3H，s)3.87(3H，s)6.69(2H，d，J＝9.0)6.77(2H，q，J＝2.2，J＝6.6)6.92(1H，dd.J＝8.8，J＝2.5)7.30～7.35(6H，m)7.38(2H，q，J＝2.2，J＝6.6)7.46(1H，d，J＝9.0)7.72(2H，d，J＝9.0)。
Embodiment 3 6-methoxyl group-2-(4-p-methoxy-phenyl)-3-[4-(4-piperazinyl)-1-benzoyl]-thionaphthene (Y-68)
1.5 gram Y-66 are dissolved in the 20mL anhydrous methanol; add 1 gram ammonium formiate and 10%Pd-C1 gram, nitrogen protection refluxed 1.5 hours down, filtered; methanol wash residue, steaming desolventize the direct silica gel column chromatography (methylene chloride 25/1) in back and obtain spumescence solid 0.70 gram.NMR(400MHz，CDCl
3)ó2.99(1H，s)3.01(4H，t)3.30(4H，t)3.73(3H，s)3.86(3H，s)6.70(2H，d，J＝9.0)6.76(2H，q，J＝2.2，J＝6.9)6.92(1H.dd.J＝2.5，J＝8.8)7.30(1H，d，J＝2.2)7.38(2H，q，J＝2.2，J＝6.9)7.46(1H，d，J＝8.8)7.73(2H，d，J＝9.0)。
Embodiment 4 6-hydroxyl-2-(4-hydroxy phenyl)-3-[4-(4-piperazinyl)-1-benzoyl]-thionaphthene (Y-77)
50mg Y-68 is dissolved in the 2mL48%HBr solution, refluxed 3 hours, reaction system is garnet, adds the saturated solution of sodium bicarbonate neutralization after reaction finishes, and at this moment system is green, extracts with ethyl acetate 20mL, and it is faint yellow that organic phase is, the green disappearance.Anhydrous sodium sulfate drying.Silica gel column chromatography (methylene chloride 8/1) obtains faint yellow solid 31mg.NMR(600MHz，DMSO-d
6)2.98(4H，br)3.36(4H，br)6.65(2H，q，J＝2.2，J＝8.8)6.79(1H，dd，J＝2.2，J＝8.8)6.84(2H，d，J＝9.5)7.13～7.16(3H，m)7.25(1H，d，J＝2.2)7.53(2H，d，J＝8.8)9.73(2H，s)。MS(EI)m/e：430(M
+)。
Embodiment 5 6-methoxyl group-2-(4-p-methoxy-phenyl)-3-[4-(4-morpholinyl)-1-benzoyl]-thionaphthene (Y-85)
Add 106mgY-69 in the 10mL reaction flask, the 1mL morpholine 100 ℃ of reactions 48 hours, is poured in the 10mL frozen water, and ethyl acetate 20mL (10x2) extraction merges organic phase, anhydrous sodium sulfate drying.Silica gel column chromatography (petrol ether/ethyl acetate 5/1) gets 111mg weak yellow foam shape solid.NMR(600MHz，CDCl
3)δ3.26(4H，t.J＝4.88)3.73(3H，s)3.86(3H，s)3.89(4H，t，J＝4.88)6.74(2H，q，J＝2.0，J＝6.8)6.86(2H，d，J＝8.8)6.93(1H，dd，J＝2.4，J＝8.8)7.29(1H，d，J＝2.2)7.33(2H，q，J＝2.0，J＝6.8)7.50(1H，d，J＝8.8)7.73(2H，d，J＝8.8)。MS(EI)m/e：459(M
+)。
Embodiment 6 6-hydroxyl-2-(4-hydroxy phenyl)-3-[4-(4-morpholinyl)-1-benzoyl]-thionaphthene (Y-88)
Y-85 104mg is dissolved in the 4mL dry methylene chloride, adds 4 of sulfur alcohols, aluminum trichloride (anhydrous) 0.32 gram.Reaction is spent the night, and steaming desolventizes, and adds THF5mL, H in system
2O5mL, ethyl acetate 10mL tells organic phase, anhydrous sodium sulfate drying.Silica gel column chromatography (methylene chloride 50/1) obtains faint yellow solid 95mg.NMR(400MHz，DMSO-d
6)δ3.26(4H，t)3.68(4H，t)6.69(2H，q，J＝1.8，J＝6.6)6.83(1H，dd，J＝2.2，J＝8.8)6.87(2H，d，J＝8.8)7.17～7.21(3H，m)7.32(1H，d，J＝2.2)7.57(2H，d，J＝8.8)9.74(1H，s)9.77(1H，s)。MS(EI)m/e：431(M
+)。
Embodiment 7 6-methoxyl group 2-(4-p-methoxy-phenyl)-3-[4-(4-methylsulfonyl piperazine)-1-benzoyls]-thionaphthene (Y-71)
90mg Y-68 is dissolved among the anhydrous THF of 2mL (dry methylene chloride), drips 4 methane sulfonyl chlorides and 4 triethylamines at 10 ℃, induction stirring 2 hours adds 20mL water, uses the 20mL dichloromethane extraction, anhydrous sodium sulfate drying.Silica gel column chromatography (methylene chloride 50/1) obtains faint yellow solid 100mg.NMR(400MHz，CDCl
3)δ2.80(3H，s)3.32(4H，t.)3.3δ(4H，t)3.74(3H，s)3.87(3H，s)6.70-6.78(4H，m)6.93(1H，dd，J＝2.4，J＝9.0)7.31(1H，d，J＝2.2)7.36(2H，q，J＝2.0，J＝6.8)7.48(1H，d，J＝8.8)7.74(2H，d，J＝9.0)。
Embodiment 8 6-hydroxyl-2-(4-hydroxy phenyl)-3-[4-(4-methylsulfonyl piperazine)-1-benzoyl]-thionaphthene (Y-132)
60mgY-71 is dissolved in the 3mL methylene dichloride, and ice bath adds boron tribromide 0.2mL down.At room temperature reaction is spent the night then.Add 4mL water quencher reaction, all dissolve to the solid precipitate, regulate PH=7 with 3NHCl then with 2N NaOH solution adjusting PH.An amount of ethyl acetate extraction, anhydrous sodium sulfate drying, silica gel column chromatography (methylene chloride 80/1) obtains the 35mg yellow solid.NMR(400MHz，DMSO-d
6)δ2.87(3H，s)3.16(4H，br)3.42(4H，br)6.68(2H，d，J＝8.0)6.82(1H，d，J＝8.4)6.88(2H，d，J＝8.4)7.16(1H，s)7.18(2H，d，J＝8.0)7.31(1H，s)7.55(2H，d，J＝8.4)9.73(1H，s)9.76(1H，s)。MS(EI)m/e：508(M
+)。
Embodiment 9 6-methoxyl group-2-(4-methoxyl group-phenyl)-3-[4-(4-p-toluenesulfonyl piperazine)-1-benzoyl]-thionaphthene (Y-72)
Operate same Y-71.NMR(400MHz，CDCl
3)δ2.42(3H，s)3.10(4H，t)3.36(4H，t)3.73(3H，s)3.87(3H，s)6.67(2H，d，J＝9.0)6.74(2H，q，J＝1.8，J＝6.8)6.92(1H，dd，J＝2.4，J＝8.8)7.30(1H，d，J＝2.4)7.32～7.35(4H，m)7.47(1H，d，J＝8.8)7.64(2H，d，J＝8.0)7.69(2H，d，J＝8.8)。MS(EI)：m/e 612(M
+)。
Embodiment 10 6-hydroxyl-2-(4-hydroxy phenyl)-3-[4-(4-p-toluenesulfonyl piperazine)-1-benzoyl]-thionaphthene (Y-130)
Operate same Y-132.NMR(400MHz，DMSO-d
6)δ2.37(3H，s)2.92(4H，br)3.37(4H，br)6.65(2H，d，J＝8.4)6.78～6.81(3H，m)7.13～7.17(3H，m)7.30(1H，d，J＝2.2)7.43(2H，d，J＝8.4)7.51(2H，d，J＝9.2)7.61(2H，d，J＝8.4)。MS(EI)：m/e584(M
+)。
Embodiment 11 6-hydroxyl-2-(4-hydroxy phenyl)-3-[4-(4-sulfanilyl radical piperazine)-1-benzoyl]-thionaphthene (Y-86)
70mg Y-73 is dissolved in the 6mL dry methylene chloride, adds 6 sulfur alcohols, 0.3 gram aluminum trichloride (anhydrous) spends the night 10 ℃ of stirrings.Steaming desolventizes, and adds THF2mL, and ethyl acetate 5mL stirs, and adds entry 10mL then, tells organic phase, water and uses ethyl acetate extraction again.Merge organic phase, use NaHCO
3The saturated solution washing, anhydrous sodium sulfate drying.Silica gel column chromatography (methylene chloride 30/1) obtains faint yellow solid 53mg.NMR(400MHz，DMSO-d
6)δ2.85(4H，br)3.35(4H，br)6.10(2H，s)6.61(2H，d，J＝8.8)6.65(2H，q，J＝1.8，J＝8.4)6.78～6.82(4H，m)7.13～7.16(3H，m)7.29(1H，d，J＝2.2)7.33(2H，d，J＝8.4)7.51(1H，d，J＝8.8)9.70(1H，s)9.74(1H，s)。MS(EI)m/e：584(M
+)。
Embodiment 12 6-methoxyl group-2-(4-p-methoxy-phenyl)-3-{4-[4-(2-furancarbonyl piperazine)]-the 1-benzoyl }-thionaphthene (Y-83)
Operate same Y-71.Silica gel column chromatography (petrol ether/ethyl acetate 1/1) obtains faint yellow solid.NMR(600MHz，CDCl
3)δ3.40(4H，t)3.73(3H，s)3.87(3H，s)4.10(4H，br)6.50(1H，q，J＝1.7，J＝3.4)6.73(2H，d，J＝8.8)6.95(1H，dd，J＝2.4，J＝9.0)7.02(2H，q，J＝8.3)7.08(1H，d，J＝2.4)7.24(1H，m)7.29(2H，q，J＝2.0，J＝8.5)7.49(1H，d，J＝0.7)7.57(1H，d，J＝9.0)7.75(2H，d，J＝8.8)。MS(EI)m/e：552(M
+)，428(100％)。
Embodiment 13 6-hydroxyl-2-(4-hydroxy phenyl)-3-{4-[4-(2-furancarbonyl piperazine)]-the 1-benzoyl }-thionaphthene (Y-84)
Operate same Y-86.Silica gel column chromatography (methylene chloride 30/1) obtains faint yellow solid.NMR(400MHz，DMSO-d
6)δ3.42(4H，t)3.76(4H，br)6.64(1H，q，J＝1.8，J＝3.4)6.67(2H，q，J＝2.0，J＝6.6)6.84(2H，d，J＝9.0)6.81(1H，q，J＝2.0，J＝9.0)7.02(1H，q，J＝0.7，J＝3.4)7.15～7.19(3H，m)7.30(1H，d，J＝2.2)7.56(2H，d，J＝9.0)7.85(1H，m，J＝0.7，J＝1.6)9.72(1H，s)9.75(1H，s)。MS(EI)m/e：524(M
+)。
Embodiment 14 6-hydroxyl-2-(4-hydroxy phenyl)-3-[4-(4-benzyl diethylenediamine-)-1-benzoyl]-thionaphthene (Y-78)
Y-66 52mg is dissolved in the 4mL dry methylene chloride, adds aluminum trichloride (anhydrous) 0.24 gram, 5 sulfur alcohols, 5 ℃ were stirred 6 hours.Drain solvent then, add 20 ml waters, 50 milliliters of extractions of ethyl acetate (25X2), NaHCO
3The saturated solution washing, anhydrous sodium sulfate drying.Silica gel column chromatography (methylene chloride 30/1) obtains faint yellow solid 50mg.NMR(600MHz，DMSO-d
6)δ2.40(4H，br)3.27(4H，br)3.45(2H，s)6.64(2H，q，J＝2.5，J＝6.5)6.77～6.81(3H，m)7.12～7.28(9H，m)7.50(2H，d，J＝8.8)9.69(1H，s)9.70(1H，s)。MS(EI)：m/e 520(M
+)。
Embodiment 15 6-methoxyl group-2-(4-p-methoxy-phenyl)-3-{4-[4-(4-benzyl chloride base piperazine)]-the 1-benzoyl }-thionaphthene (Y-112)
61mg Y-68 and 100mg are dissolved among the 4mLTHF bromine chloride, add 7 of diisopropylethylamine, stir under the room temperature and spend the night.Reaction solution is poured in the water, uses an amount of ethyl acetate extraction, anhydrous sodium sulfate drying, and silica gel column chromatography (petrol ether/ethyl acetate 3/1) obtains faint yellow solid 71mg.NMR(400MHz，DMSO-d
6)δ2.41(4H，br)3.28(4H，br)3.47(2H，s)3.70(3H，s)3.81(3H，s)6.84(2H，d，J＝8.8)6.89(2H，d，J＝8.8)6.95(1H，dd，J＝2.6，J＝8.8)7.23(1H，d，J＝8.8)7.31～7.36(6H，m)7.54(2H，d，J＝8.8)7.62(1H，d，J＝2.6)。MS(EI)：m/e582(M
+)。
Embodiment 16 6-methoxyl group-2-(4-p-methoxy-phenyl)-3-{4-[4-(pyridine-4-formyl piperazine)]-the 1-benzoyl }-thionaphthene (Y-109)
With DCC60mg, HOBt40mg, Yi Yansuan 30mg is dissolved in anhydrous THF4mL, at room temperature stirs 20 minutes, adds 61mgY-68 again, and reaction is spent the night.Drain solvent, silica gel column chromatography (methylene chloride 50/1) obtains faint yellow solid 58mg.NMR(400MHz，CDCl
3)δ3.29(2H，br)3.43(2H，br)3.49(2H，br)3.75(3H，s)3.89(3H，s)3.92(2H，br)6.72(2H，d，J＝9.2)6.77(2H，d，J＝8.8)6.94(1H，dd，J＝2.4，J＝8.8)7.32(1H，d，J＝2.4)7.36(2H，d，J＝8.8)7.49(1H，d，J＝8.8)7.60(2H，br)7.75(2H，d，J＝8.8)8.80(2H，br)。MS(EI)：m/e 563(M
+)。
Embodiment 17 6-hydroxyl-2-(4-hydroxy phenyl)-3-{4-[4-(pyridine-4-formyl piperazine)]-the 1-benzoyl }-thionaphthene (Y-113)
Operate same Y-86.Silica gel column chromatography (methylene chloride 25/1) obtains 50mg.NMR(400MHz，DMSO-d
6)δ3.45(4H，br)3.70(4H，br)6.67(2H，q，J＝2.2，J＝8.8)6.80(1H，d，J＝2.57)6.84(2H，d，J＝8.8)7.17～7.19(3H，m)7.31(1H，d，J＝2.2)7.41(2H，q，J＝1.8，J＝4.4)7.55(2H，d，J＝9.2)8.66(2H，d，J＝5.9)9.73(1H，s)9.76(1H，s)。MS(EI)：m/e535(M
+)
Embodiment 18 6-methoxyl group-2-(4-p-methoxy-phenyl)-3-{4-[4-(4-, the piperazine of 6-dimethyl pyrimidine-2-)-]-the 1-benzoyl }-thionaphthene (Y-138)
70mgY-68 is dissolved in the 3mL dehydrated alcohol, adds 4.6-dimethyl-2-chloro-pyrimidine, diisopropylethylamine, backflow is spent the night, and drains solvent, and silica gel column chromatography (methylene chloride 25/1) obtains 73mg.NMR(400MHz，CDCl
3)δ2.49(6H，s)3.46(4H，br)3.75(3H，s)3.88(3H，s)4.14(4H，br)6.40(1H，s)6.73(2H，d，J＝9.0)6.77(2H，q，J＝2.0，J＝6.8)6.94(1H，dd，J＝24，J＝8.8)7.32(1H，d，J＝2.2)7.38(2H，q，J＝2.0，J＝6.8)7.49(1H，d，J＝8.8)7.75(2H，d，J＝8.8)。MS(EI)：m/e564。
Embodiment 19 6-hydroxyl-2-(4-hydroxybenzene)-3-{4-[4-(4-, the piperazine of 6-dimethyl pyrimidine-2-)-]-the 1-benzoyl }--thionaphthene (Y-140)
Operate same Y-118b, silica gel column chromatography (methylene chloride 501) obtains faint yellow solid.NMR(400MHz，DMSO-d
6)δ2.21(6H，s)3.42(4H，br)3.80(4H，br)6.42(1H，s)6.68(2H，d，J＝8.4)6.82(1H，dd，J＝1.8，J＝8.8)6.86(2H，d，J＝9.2)7.18(2H，d，J＝8.4)7.19(1H，d，J＝8.8)7.31(1H，d，J＝1.8)7.56(2H，d，J＝8.8)9.72(1H，s)9.75(1H，s)。MS(EI)：m/e536。
Embodiment 20 6-methoxyl group-2-(4-p-methoxy-phenyl)-3-[4-(4-sec.-propyl piperazine)-1-benzoyl]-thionaphthene (Y-133)
60mgY-68 is dissolved in the anhydrous THF of 2mL, adds 4 of tosic acid isopropyl esters, salt of wormwood 43mg refluxed 24 hours, drained solvent, and silica gel column chromatography (methylene chloride 80/1) obtains faint yellow solid 54mg.NMR(400MHz，CDCl
3)δ1.26(6H，d，J＝4.7)3.00(4H，br)3.40(1H，m)3.66(4H，br)3.75(3H，s)3.87(3H，s)6.69(2H，d，J＝9.0)6.76(2H，q，J＝2.0，J＝6.7)6.94(1H，dd，J＝2.5，J＝8.9)7.31(1H，d，J＝2.2)7.35(2H，q，J＝2.0，J＝6.7)7.49(1H，d，J＝8.8)7.73(2H，d，J＝9.0)。
Claims (4)
1. the following benzothienyl compounds of a class formation formula
Or the physiologically acceptable salt shown in the formula I,
R wherein
1=R
2=OH, Y=-C=O, X=N,
R
3Be H, HC (CH
3)
2, 4-chloro-benzyl ,-chlorobenzene formacyl, right-chlorobenzene formacyl ,-methyl benzoyl, to nitrobenzyl, the 4-methylsulfonyl, the 4-p-toluenesulfonyl, the 4-sulfanilyl radical, the 2-furancarbonyl, pyridine-4-formyl radical, or 4,6-dimethyl pyrimidine-2-base.
2. the preparation method of benzothienyl compounds as claimed in claim 1 is characterized in that
A ,-the methoxyl group thiophenol with to methoxyl group-ω-bromoacetophenone reacting generating compound A under alkaline condition, i.e. 4-methoxyl group-ω-(3-p-methoxy-phenyl-sulfo-) methyl phenyl ketone;
B, compd A generate intermediate B, i.e. 2-(4-p-methoxy-phenyl)-6-methoxyl group-thionaphthene through polyphosphoric acid effect generation cyclization and isomerization;
The reaction in the presence of Lewis acid and to fluorobenzoyl chloride of c, compd B obtains intermediate C, i.e. 6-methoxyl group-2-(4-p-methoxy-phenyl)-3-(4-fluoro-benzoyl)-thionaphthene;
D, intermediate C and Piperazine anhydrous react compd E, i.e. 6-methoxyl group-2-(4-p-methoxy-phenyl)-3-[4-(4-piperazinyl)-1-benzoyl]-thionaphthene, or with the benzyl diethylenediamine reaction, debenzylation gets compd E again;
E, intermediate E are the R of carboxylic acid halides, acid anhydrides, halogenide or sulphonate again with active group
3Reaction, the deprotection base gets benzothienyl compounds again, R
3Definition according to claim 1.
3. according to the preparation method of the described benzothiophenes of claim 2, it is characterized in that deprotection base in the presence of aluminum chloride/sulfur alcohol or tribromo boron.
4. the purposes of benzothiophenes as claimed in claim 1 is used in the medicine of preparation selective estrogen receptor adjusting activity, prevent and treat women's post-menopause syndrome.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4133814A (en) * | 1975-10-28 | 1979-01-09 | Eli Lilly And Company | 2-Phenyl-3-aroylbenzothiophenes useful as antifertility agents |
| US4418068A (en) * | 1981-04-03 | 1983-11-29 | Eli Lilly And Company | Antiestrogenic and antiandrugenic benzothiophenes |
| EP0729956A1 (en) * | 1995-02-28 | 1996-09-04 | Eli Lilly And Company | Benzothiophene compounds, intermediates, compositions, and methods |
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2003
- 2003-05-16 CN CN 03116995 patent/CN1548434B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4133814A (en) * | 1975-10-28 | 1979-01-09 | Eli Lilly And Company | 2-Phenyl-3-aroylbenzothiophenes useful as antifertility agents |
| US4418068A (en) * | 1981-04-03 | 1983-11-29 | Eli Lilly And Company | Antiestrogenic and antiandrugenic benzothiophenes |
| EP0729956A1 (en) * | 1995-02-28 | 1996-09-04 | Eli Lilly And Company | Benzothiophene compounds, intermediates, compositions, and methods |
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