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Indole derivatives useful for the treatment of osteoporosis

A technology of indoles and drugs, applied in the field of new compounds, capable of solving impossible problems

Inactive Publication Date: 2005-06-29
NIKEM RES S R L MILANO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But Baron's study was done in chicks, and Hall et al. (Bone and Mineral 27, 159-166, (1994)) concluded in a study involving mammals that : In contrast to avian osteoclast V-ATPase, mammalian osteoclast V-ATPase has similar pharmacological properties to V-ATPase in other cells and is therefore unlikely to be a good therapeutic target

Method used

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  • Indole derivatives useful for the treatment of osteoporosis
  • Indole derivatives useful for the treatment of osteoporosis
  • Indole derivatives useful for the treatment of osteoporosis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0213] Example 1: 4-(5,6-dichloro-1H-indol-2-yl)-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)benzamide

[0214]

[0215]4-(5,6-dichloro-1H-indol-2-yl)benzoic acid (0.25g, 0.82mmol), WSC (0.156g, 0.82mmol), HOAT (0.11g, 0.82mmol), 4- A mixture of amino-1,2,2,6,6-pentamethylpiperidine (0.209 g, 1.2 mmol), DIEA (0.212 g, 1.2 mmol) in DMF (3 ml) was stirred at room temperature for 16 hours. The mixture was then poured into water, made basic by addition of NaOH N and extracted with ethyl acetate. The organic solution was washed with water, dried over magnesium sulfate, concentrated in vacuo, and the residue was purified by column chromatography (silica gel; chloroform / methanol / ammonium hydroxide; 9 / 1 / 0.1) to obtain 0.35 g (0.76 mmol, 93% yield) of The title compound was in the form of white crystals, melting point = 325°C.

[0216] 1 H-NMR (DMSO-d 6 )δ=11.98(s, 1H); 8.26(d, 1H); 7.95(m, 4H); 7.82(s, 1H); 7.6(s, 1H); 7.05(s, 1H); ); 2.19(s, 3H); 1.71(m, 2H); 1.48(m, 2H); 1.10(s, ...

Embodiment 2

[0217] Example 2: 4-(5,6-dichloro-1H-indol-2-yl)-3-methoxy-N-(1,2,2,6,6-pentamethylpiperidine-4 -yl)benzamide

[0218]

[0219] 3-Methoxy-4-(5,6-dichloro-1H-indol-2-yl)benzoic acid (0.15g, 0.45mmol), WSC (0.094g, 0.5mmol), HOAT (0.067g, A mixture of 0.5 mmol), 4-amino-1,2,2,6,6-pentamethylpiperidine (0.15 g, 0.9 mmol) in DMF (2 ml) was stirred at 50° C. for 18 hours. The mixture was then poured into a large amount of water and extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, concentrated in vacuo and the residue is purified by flash chromatography (silica gel; dichloromethane / methanol / ammonium hydroxide; 91.5 / 7.5 / 1) and then crystallized in diisopropyl ether to give 0.13 g (0.26 mmol, 59% yield) of the title compound, melting point = 260°C.

[0220] 1 H NMR (DMSO-d 6 )δ=11.58(s, 1H); 8.26(d, 1H); 7.88(d, 1H); 7.82(s, 1H); 7.67(s, 1H); 7.57(m, 2H); ); 4.22(m, 1H); 4.02(s, 3H); 2.20(s, 3H); 1.73(m, 2H); 1.46(m, 2H); 1.1...

Embodiment 3

[0221] Example 3: 4-(5,6-dichloro-1H-indol-2-yl)-2-methoxy-N-(1,2,2,6,6-pentamethylpiperidine-4 -yl)benzamide

[0222]

[0223] Starting from the corresponding 2-methoxy-4-(5,6-dichloro-1H-indol-2-yl)benzoic acid, this compound was obtained by the same method.

[0224] 1 H NMR (DMSO-d 6 )δ=11.98(s, 1H); 7.91(d, 1H); 7.82(s, 1H); 7.77(d, 1H); 7.56(m, 3H); 7.08(s, 1H); ); 4.00(s, 3H); 2.19(s, 3H); 1.75(m, 2H); 1.38(m, 2H); 1.10(s, 6H); 1.05(s, 6H).

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Abstract

A compound of formula (I) or its salt or solvate: wherein: A represents an optionally substituted aryl or an optionally substituted heterocyclic group; Ra represents -CO-NRsRt, wherein Rs and Rt each independently represent hydrogen, alkyl , substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or Rs and Rt Together with the nitrogen atoms connected to them, they form a heterocyclic group; R1 and R2 each independently represent hydrogen, hydroxyl, amino, alkoxy, optionally substituted aryloxy, optionally substituted benzyloxy, alkylamino, Dialkylamino, halogen, trifluoromethyl, trifluoromethoxy, nitro, alkyl, carboxyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, or R1 and R2 together represent methylenedioxy radical, carbonyldioxy, carbonyldiamino; and R3 represents hydrogen, alkanoyl, alkyl, aminoalkyl, hydroxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, carbamoyl or alkylsulfonyl Acyl and arylsulfonyl groups; processes for preparing such compounds, pharmaceutical compositions containing such compounds and the use of such compounds or compositions in medicine. ∴

Description

technical field [0001] The present invention relates to certain novel compounds, methods for preparing such compounds, pharmaceutical compositions containing such compounds and the use of such compounds and compositions in medicine. Background technique [0002] Diseases associated with bone loss are known to result from overactivity of osteoclasts. Certain compounds commonly related to bafilomycin are also known to be useful in the treatment of such diseases: for example International Patent Application Publication No. WO 91 / 06296 discloses certain bafilomycin macrolides useful in the treatment of bone diseases. [0003] However, bafilomycin derivatives are not selective for human osteoclasts. Therefore, the use of these compounds is associated with unacceptable toxicity due to the broad blockade of other essential v-ATPases. Indeed, no treatment selective for human osteoclasts is known to date. [0004] The search for successful treatments for human diseases associated ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12A61K31/40C07D209/18A61P19/10A61K31/403A61K31/404A61K31/4427A61K31/454A61K31/496A61P1/04A61P3/06A61P9/10A61P25/28A61P31/12A61P35/00A61P37/06
CPCC07D209/18C07D401/12A61P1/04A61P19/10A61P25/28A61P31/12A61P35/00A61P3/06A61P37/06A61P9/10A61K31/454A61K31/496
Inventor S·加格利尔蒂G·M·M·G·纳德勒P·诺韦拉
Owner NIKEM RES S R L MILANO