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WO1999054325A1 - Derives 1-heteroindene et compositions medicinales a base de tels derives - Google Patents

Derives 1-heteroindene et compositions medicinales a base de tels derives Download PDF

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Publication number
WO1999054325A1
WO1999054325A1 PCT/JP1999/002037 JP9902037W WO9954325A1 WO 1999054325 A1 WO1999054325 A1 WO 1999054325A1 JP 9902037 W JP9902037 W JP 9902037W WO 9954325 A1 WO9954325 A1 WO 9954325A1
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WO
WIPO (PCT)
Prior art keywords
group
compound
tlc
yield
title compound
Prior art date
Application number
PCT/JP1999/002037
Other languages
English (en)
Japanese (ja)
Inventor
Masashi Ogawa
Tadashi Morita
Norihiro Iibuchi
Hideaki Suzuki
Hideyuki Tsutsui
Atsuyuki Kano
Satoru Kato
Original Assignee
Senga Pharmaceutical Laboratory Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Senga Pharmaceutical Laboratory Inc. filed Critical Senga Pharmaceutical Laboratory Inc.
Priority to AU31710/99A priority Critical patent/AU3171099A/en
Publication of WO1999054325A1 publication Critical patent/WO1999054325A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/56—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/80—Radicals substituted by oxygen atoms

Definitions

  • Examples of the pharmaceutically acceptable salt of the compound represented by the formula (I) include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, nitric acid, pyrosulfuric acid, and metaphosphoric acid. Acid or an organic acid such as citric acid, benzoic acid, acetic acid, propionic acid, fumaric acid, maleic acid, sulfonic acid (for example, methanesulfonic acid, ⁇ -toluenesulfonic acid, naphthalenesulfonic acid); . In addition, when it has a phenolic hydroxy group, it can be used as an alkali metal salt such as sodium salt and potassium salt.
  • inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, nitric acid, pyrosulfuric acid, and metaphosphoric acid.
  • Acid or an organic acid such as citric acid
  • R 8 represents a methylene group or a carbonyl group
  • R 2 ′ is located on the R 2 side and represents a direct bond or a methylene group.
  • a binder In this type of preparation, a binder, a disintegrant, a surfactant, a lubricant, a fluidity promoter, a flavoring agent, a coloring agent, a fragrance, and the like can be appropriately used in addition to the above-mentioned excipients.
  • binders include starch, dextrin, gum arabic, gelatin, hydroxypropyl starch, methylcellulose, carboxymethylcellulose—sodium, hydroxypropylcellulose, crystalline cellulose, ethylcellulose Loin, polyvinylpyrrolidone and macrogol.
  • ⁇ Disintegrators include, for example, starch, hydroxypropyl starch, sodium carboxymethylcellulose, calcium carboxymethylcellulose, carboxymethylcellulose, and low-substituted hydroxypropylcellulose.
  • Example 1 2-promote 5-methoxy) phenethyl-5- (4-methoxyphenyl) indole-3-carbaldehyde
  • Example 13 Using 2.00 g of the compound obtained in Example 13 as a raw material, 1.32 g of the title compound was obtained as pale brown crystals in the same manner as in Example 7 (80% yield).
  • Example 60 Using 300 mg of the compound obtained in Example 60 as a raw material, 276 mg of the title compound was obtained as yellow crystals in the same manner as in Example 22 (yield: 81%).
  • Example 68 Using the compound obtained in Example 68 as a starting material, the title compound was obtained as yellow crystals in the same manner as in Example 7 (yield: 84%).
  • Example 73 Using the compound obtained in Example 73 as a raw material, the title compound was obtained as pale yellow crystals in the same manner as in Example 7 (yield: 88%).
  • M dimethylformamide 3
  • 340 mg of tetrakis (triphenylphosphine) palladium and 640 mg of acetic acid potassium were added, and the mixture was stirred at 110 °
  • Example 90 Using 170 mg of the compound obtained in Example 90 as a raw material, 77 mg of the title compound was obtained as dark red-brown crystals in the same manner as in Example 9 (yield: 48%).
  • Example 89 Using 120 mg of the compound B obtained in Example 88 as a raw material, 100 mg of the title compound was obtained as brown crystals in the same manner as in Example 89 (95% yield).
  • Example 93 Using 100 mg of the compound obtained in Example 93 as a raw material, 66 mg of the title compound was obtained as brown crystals in the same manner as in Example 9 (yield: 68%).
  • Example 95 Using 3.6 g of the compound obtained in Example 95 as a raw material, 8 g of the title compound was obtained as brown crystals in the same manner as in Example 87 (yield: 63%).
  • Example 9 73,9-Dimethyloxy 111- [methoxy (methoxymethyloxy) benzoyl] -6H-isoindolo [2,1-a] indole (compound A) and 3,9-dimethyloxy — 1 1 — [4- (Methoxymethoxyloxy) benzoyl] -6—oxo 6 H—isoindolo [2,1-a] indole (Compound B)
  • Example 1 00 3,9-dihydroxy-1 1 1 — ⁇ 4- [2- (1—piveridyl) ethoxy] benzoyl-1 6H-isoindolo [2,1—a] indole Obtained in Example 99 Using the compound (200 mg) as a raw material, 150 mg of the title compound was obtained as brown crystals in the same manner as in Example 9 (yield 79%).
  • Example 97 Using 250 mg of the compound B obtained in Example 97 as a raw material, 220 mg of the title compound was obtained as brown crystals in the same manner as in Example 89 (yield: 98%).
  • Example 1023 3,9-Dimethoxy-1 1 1 4- 1 [2- (1-Piperidyl) ethoxy] benzoyl-6-oxo-1 6H-isoindolo [2,1—a] indole Using the compound (250 nig ) obtained in Example i01 as a raw material, 280 mg of the title compound was obtained as brown crystals in the same manner as in Example 90 (yield: 88%).
  • Example 102 Using 250 mg of the compound obtained in Example 102 as a raw material, 160 mg of the title compound was obtained as brown crystals in the same manner as in Example 9 (yield: 68%).
  • Example 108 Using 156 mg of the compound obtained in Example 108 as a raw material, 120 mg of the title compound was obtained as brown crystals in the same manner as in Example 90 (yield: 62%).
  • HOS cells (Dainippon Pharmaceutical)-Dulbecco's modified Eagle's medium (DMEM) (I CN)
  • FBS is treated with DCC to remove endogenous estrogens by DCC treatment.
  • H ⁇ S cells were cultured in DMEM containing 10% DCC-FBS in T-75 flasks. When the cells reached confluence, 30,000 cells were seeded per well on a 24-well culture plate, and cultivation was continued in the same medium. One day later, the medium was changed to MEM containing 10% DCC-FBS, and treatment with raloxifene or the compound of the present invention was started at a concentration of 100 nM. The medium was changed on the third day, and the medium at the time of the medium change on the sixth day was collected as Conditioned Medium (CM).
  • CM Conditioned Medium
  • Fetal Serum Fetal Serum (FBS) (Gibco) ⁇ 3-Estradiol (estrogen) (Sigma).
  • DCC Dextran-coated activated carbon
  • test compound since the effect of the test compound is not exerted at all in the absence of estrogen, it is considered that the test compound does not act as an agonist on the proliferation of MCF-7 cells.
  • the treatment with estrogen alone increased the number of cells about 2-fold at a concentration of 1 nM or more.
  • the compounds and pharmaceutical compositions of the present invention are useful as estrogen receptor modulators, and include, for example, diseases caused by decreased estrogen, particularly osteoporosis, cardiovascular diseases, hyperlipidemia, It is useful for the prevention and treatment of various symptoms such as cholesterolemia and menopause.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention, qui concerne des composés représentés par la formule générale (I) ou certains de leurs sels, concerne également une composition médicinale contenant n'importe lesquels de ces composés, et plus particulièrement un régulateur de récepteur d'oestrogène ainsi qu'un médicament anti-ostéoporose. En l'occurrence, R1 est un groupe aromatique éventuellement substitué, hydroxyle ou alcoxy. X est soufre ou oxygène, auquel cas R2 est hydrogène. Mais X peut former, en coopération avec R2, un groupe représenté par la formule spécifique (A) N-R8-R2'. Pour cette dernière, R8 est méthylène ou carbonyle, R2' étant une liaison directe du méthylène. R3 est hydrogène, halogène, hydroxy, alcoxy, ou un groupe aromatique éventuellement substitué. R4 est carbonyle ou hydroxyméthylène. R5 est alkylène, et R6 ainsi que R7 sont alkyle ou, en coopération, alkylène.
PCT/JP1999/002037 1998-04-17 1999-04-16 Derives 1-heteroindene et compositions medicinales a base de tels derives WO1999054325A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU31710/99A AU3171099A (en) 1998-04-17 1999-04-16 1-heteroindene derivatives and medicinal composition containing the same

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP10726398 1998-04-17
JP10/107263 1998-04-17

Publications (1)

Publication Number Publication Date
WO1999054325A1 true WO1999054325A1 (fr) 1999-10-28

Family

ID=14454624

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1999/002037 WO1999054325A1 (fr) 1998-04-17 1999-04-16 Derives 1-heteroindene et compositions medicinales a base de tels derives

Country Status (2)

Country Link
AU (1) AU3171099A (fr)
WO (1) WO1999054325A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002016338A1 (fr) * 2000-08-23 2002-02-28 Sanofi-Synthelabo Aminoalkenylbenzoyl-benzofuranes ou benzothiophenes, leur procede de preparation et les compositions les contenant
WO2006073715A3 (fr) * 2004-12-31 2007-05-31 Aventis Pharma Inc Utilisation de composes choisis pour proteger des neurones et des oiligodendrocytes lors du traitement de la sclerose en plaques

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS57181081A (en) * 1981-04-03 1982-11-08 Lilly Co Eli 3-(4-aminoethoxybenzoyl)benzo(b)thiophene compound
JPH07267858A (ja) * 1994-01-28 1995-10-17 Eli Lilly & Co 骨粗しょう症の組み合せ治療法
JPH08511273A (ja) * 1993-10-12 1996-11-26 ファイザー・インク． エストロゲン作動薬としてのベンゾチオフェンと関連化合物
JPH08333366A (ja) * 1995-06-07 1996-12-17 Eli Lilly & Co 窒素含有非塩基性側鎖を有する化合物および医薬組成物
JPH09507071A (ja) * 1993-12-21 1997-07-15 イーライ・リリー・アンド・カンパニー アミロイド原性ペプチドに関連した状態を治療又は予防する方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS57181081A (en) * 1981-04-03 1982-11-08 Lilly Co Eli 3-(4-aminoethoxybenzoyl)benzo(b)thiophene compound
JPH08511273A (ja) * 1993-10-12 1996-11-26 ファイザー・インク． エストロゲン作動薬としてのベンゾチオフェンと関連化合物
JPH09507071A (ja) * 1993-12-21 1997-07-15 イーライ・リリー・アンド・カンパニー アミロイド原性ペプチドに関連した状態を治療又は予防する方法
JPH07267858A (ja) * 1994-01-28 1995-10-17 Eli Lilly & Co 骨粗しょう症の組み合せ治療法
JPH08333366A (ja) * 1995-06-07 1996-12-17 Eli Lilly & Co 窒素含有非塩基性側鎖を有する化合物および医薬組成物

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002016338A1 (fr) * 2000-08-23 2002-02-28 Sanofi-Synthelabo Aminoalkenylbenzoyl-benzofuranes ou benzothiophenes, leur procede de preparation et les compositions les contenant
FR2813307A1 (fr) * 2000-08-23 2002-03-01 Sanofi Synthelabo Aminoalkenylbenzoyl-benzofurannes ou benzothiophenes, leur procede de preparation et les compositions les contenant
US6946483B2 (en) 2000-08-23 2005-09-20 Sanofi-Aventis Aminoalkenylbenzoyl-benzofuran or benzothiophene, method for preparing same and compositions containing same
WO2006073715A3 (fr) * 2004-12-31 2007-05-31 Aventis Pharma Inc Utilisation de composes choisis pour proteger des neurones et des oiligodendrocytes lors du traitement de la sclerose en plaques

Also Published As

Publication number Publication date
AU3171099A (en) 1999-11-08

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