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Treatment of central nervous system disorders with selective estrogen receptor modulators

A central nervous system, patient technology, applied in the medical field, can solve problems such as increasing reproductive tissue cancer

Inactive Publication Date: 2000-07-19
ELI LILLY & CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the potential for estrogen replacement therapy is outweighed by the increased risk of reproductive tissue cancer associated with the disadvantages of long-term estrogen therapy

Method used

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  • Treatment of central nervous system disorders with selective estrogen receptor modulators

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preparation example Construction

[0062] The preparation of the ester prodrug compound of formula I is by, with formula-OCO-(C 1 -C 6 Alkyl) group or -OSO 2 (C 2 -C 6 Alkyl) groups displace any hydroxyl groups that may be present in the 6- and / or 4'-position by known methods, see, for example, US Pat. No. 4 358 593.

[0063] For example, when -OCO-(C 1 -C 6 Alkyl) is the desired group and a mono- or di-hydroxyl compound of formula I is reacted with reagents such as acid chlorides, bromides, cyanides or azides, or with appropriate anhydrides or mixed anhydrides. The reaction is usually carried out in a basic solvent such as pyridine, lutidine, quinoline or isoquinoline, or in a tertiary amine solvent such as triethylamine, tributylamine, methylpiperidine and the like. This reaction can also be reacted in an inert solvent such as ethyl acetate, dimethylformamide, dimethyl sulfoxide, dioxane, dimethoxyethane, acetonitrile, acetone, methyl ethyl ketone, etc., in such an inert solvent should have added at le...

Embodiment 1

[0114] Example 1 [6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-(4-methoxyphenyl)]benzo[ b] Preparation of Thiophene Oxalate Step a: Preparation of [6-methoxy-2-(4-methoxy-phenyl)-3-bromo]benzo[b]thiophene

[0115] At 60°C, to a solution of [6-methoxy-2-(4-methoxyphenyl)]benzo[b]thiophene (27.0g, 100mmol) dissolved in 1.10L chloroform was added dropwise Bromine (15.98 g, 100 mmol) solution in 200 mL chloroform. After the addition was complete, the reaction was cooled to room temperature, and the solvent was removed in vacuo to afford 34.2 g (100%) of [6-methoxy-2-(4-methoxyphenyl)-3-bromo]benzo[b ] Thiophene as a white solid. mp 83-85℃. 1 H NMR (DMSO-d6)d 7.70-7.62 (m, 4H), 7.17 (dd, J=8.6, 2.0Hz, 1H), 7.09 (d, J=8.4Hz, 2H). FD mass spectrum: 349, 350. Theoretical value: C 16 h 13 o 2 SBr: C, 55.03; H, 3.75. Found: C, 54.79; H.3.76. Step b): [6-methoxy-2-(4-methoxyphenyl)-3-(4-benzyl Preparation of oxy)phenoxy]benzo[b]thiophene

...

Embodiment 2

[0119] Example 2 [6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-(4-methoxyphenyl)]benzo[ b] Preparation of thiophene hydrochloride

[0120] Treatment of the oxalate salt of Example 1 with aqueous base to generate its free base, followed by reaction with diethyl ether saturated with hydrochloric acid, afforded the title salt. mp 216-220°C. 1 H NMR (DMSO-d6)d 10.20(bs, 1H), 7.64(d, J=8.7Hz, 2H), 7.59(d, J=1.5Hz, 1H), 7.18(d, J=9.0Hz, 1H) , 7.00.(d, J=8.7Hz, 1H), 6.96(dd, J=9.0, 1.5Hz, 1H), 6.92(q, J AB=9.0Hz, 4H), 4.31(m, 2H), 3.83(s, 3H), 3.77(s, 3H), 3.43(m, 4H), 2.97(m, 2H), 1.77(m, 5H), 1.37 (m, 1H). FD mass spectrum: 489. Theoretical value C 29 h 31 NO 4 S.1.0 HCl: C, 66.21; H, 6.13; N, 2.66. Found: C, 66., 46; H, 6.16; N, 2.74.

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Abstract

The present invention provides a method of treating depression, mood swings, or Alzheimer's disease in a patient in need of such treatment by administering a selective estrogen receptor modulating compound of the formula in which R1 and R2 are independently hydroxy and alkoxy of one to four carbon atoms; and R3 and R4 are independently methyl or ethyl, or R3 and R4, taken together with the nitrogen atom to which they are attached, form a pyrrolidino, methyl-pyrrolidino, dimethylpyrrolidino, piperidino, morpholino, or hexamethyleneimino ring.

Description

technical field [0001] This application relates to medical methods. More specifically, the present invention relates to the use of a class of substituted benzo[b]thiophene compounds for the treatment of patients suffering from depression, mood lability and Alzheimer's disease. Background of the invention [0002] In addition to the well established effects of estrogen on reproductive tissue, bone, and cholesterol metabolism in postmenopausal women, estrogen is also known to have numerous effects on the central nervous system with somatic and behavioral consequences. [0003] In menopausal women, anxiety, depression, nervousness, and excitement begin around menopause and may be related to decreased estrogen levels. Estrogen replacement therapy has been recommended for the treatment of these symptoms (see J. Malleson, Lancet, 2: 158 (1953) and R. Wilson, et al., J. Am. Geriatric Soc., 11: 347 (1963)). [0004] The mechanism of estrogen's protective eff...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/64A61K31/381A61K31/4025A61K31/4535A61K31/5377A61K31/55A61P25/24A61P25/28
CPCY10S514/878A61K31/4535A61K31/5377A61K31/381Y10S514/879A61K31/4025A61K31/55A61P25/18A61P25/24A61P25/28A61K31/38
Inventor K·R·巴勒斯H·U·布赖安特S·M·保尔M·P·克纳德勒
Owner ELI LILLY & CO
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