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Disubstituted [4-(5-aminomethyl-phenyl)-piperidin-1-yl]-1h-indol-3-yl]-methanones

An aminomethyl group and substituent technology, which can be used in metabolic diseases, medical preparations containing active ingredients, allergic diseases, etc., and can solve the problems of compounds with low activity

Inactive Publication Date: 2012-05-23
SANOFI SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0021] Bioorg. Med. Chem. Lett. 15 , 2734 (2005) also disclosed that substitution at the 5th or 7th aromatic carbon atom on indole is acceptable, whereas substitution at the 4th or 6th position produces less active compounds

Method used

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  • Disubstituted [4-(5-aminomethyl-phenyl)-piperidin-1-yl]-1h-indol-3-yl]-methanones
  • Disubstituted [4-(5-aminomethyl-phenyl)-piperidin-1-yl]-1h-indol-3-yl]-methanones
  • Disubstituted [4-(5-aminomethyl-phenyl)-piperidin-1-yl]-1h-indol-3-yl]-methanones

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0149] [4-(5-aminomethyl-2-fluoro-phenyl)-piperidin-1-yl]-[5-chloro-1-(2-methoxy-ethyl)-7-methyl-1H -Indol-3-yl]-methanone hydrochloride

[0150]

[0151] A. 2,2,2-Trifluoro-N-(4-fluoro-3-pyridin-4-yl-benzyl)-acetamide hydrochloride

[0152]

[0153] Add NaHCO to the flask at room temperature 3(126g, 1.5mol), 3-bromo-4-fluorobenzylamine hydrochloride (120g, 0.5mol) and pyridine-4-boronic acid (67.6g, 0.55mmol) and isopropanol (750mL) and water (375mL) . The suspension was degassed with nitrogen at 10 °C for 1.0 h. To this mixture was added 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloromethane complex (PdCl 2 dppf-CH 2 Cl 2 , 16.4g, 20mmol). The reaction mixture was heated to 80 °C, a portion was distilled off until the internal temperature reached 80 °C, and stirred for 10 h. After completion of the reaction (HPLC analysis), the mixture was cooled to room temperature, then 2N aqueous HCl (750 mL) was added and stirred for 0.5 h. use CH 2 Cl 2 (750 ...

Embodiment 2

[0176] [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1-yl]-[6-fluoro-1-(2-methoxy-ethyl)-7-methyl -1H-indol-3-yl]-methanone hydrochloride

[0177]

[0178] A.1-(2-Amino-4-fluoro-3-methyl-phenyl)-2-chloro-ethanone

[0179]

[0180] The title compound was prepared following the procedure described by Glennon, R.A. et al. J. Med. Chem. 1980, 23, 1222-1226 using 3-fluoro-2-methylaniline as starting material. 1 H NMR (CD 3 CN) δ 7.65-7.60 (m, H), 6.84 (bs, 2H), 6.44-6.38 (m, H), 4.77 (s, 2H), 2.02 (m, 3H).

[0181] B. 6-Fluoro-7-methyl-1H-indole

[0182]

[0183] Using 1-(2-amino-4-fluoro-3-methyl-phenyl)-2-chloro-ethane according to the procedure described by Glennon, R.A. et al.J.Med.Chem. The title compound was prepared from the ketone as starting material. 1 H NMR (CD 3 CN) δ9.32(bs, 1H), 7.38-7.34(m, 1H), 7.25-7.23(m, 1H), 7.85-7.78(m, 1H), 6.46-6.44(m, 1H), 2.38(s , 3H).

[0184] C. 6-fluoro-1-(2-methoxy-ethyl)-7-methyl-1H-indole

[0185]

[0186]...

Embodiment 3

[0200] [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1-yl]-[5-fluoro-1-(2-methoxy-ethyl)-7-methyl -1H-indol-3-yl]-methanone hydrochloride

[0201]

[0202] A.1-(2-Amino-5-fluoro-3-methyl-phenyl)-2-chloro-ethanone

[0203]

[0204] The title compound was prepared in a similar manner to Example 2A, using 4-fluoro-2-methyl-aniline as a starting material. 1 H NMR (CD 3 CN): δ 7.32-7.28 (m, 1H), 7.13-7.09 (m, 1H), 6.51 (bs, 2H), 4.78 (s, 2H), 2.12 (s, 3H).

[0205] B. 5-Fluoro-7-methyl-1H-indole

[0206]

[0207] The title compound was obtained in a similar manner to Example 2B, using 1-(2-amino-5-fluoro-3-methyl-phenyl)-2-chloro-ethanone as a starting material. 1 H NMR (CD 3 CN): δ9.32(bs, 1H), 7.30(t, 1H), 7.12-7.08(m, 1H), 6.78-6.74(m, 1H), 6.46-6.44(m, 1H), 2.47(s, 3H).

[0208] C. 5-fluoro-1-(2-methoxy-ethyl)-7-methyl-1H-indole

[0209]

[0210] The title compound was obtained in a similar manner to Example 1D, using 5-fluoro-7-methyl-1H-indole as a s...

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Abstract

The present invention extends to the compound of formula I: or a prodrug, pharmaceutically acceptable salt, or solvate of said compound. Furthermore, the present invention is directed to a pharmaceutical composition comprising a pharmaceutically effective amount of the compound of formula I, and a pharmaceutically acceptable carrier. Furthermore, the present invention is directed to the use of a compound of formula I as an inhibitor of tryptase, comprising introducing the compound into a composition comprising tryptase. In addition, the present invention is directed to the use of a compound of formula I for treating a patient suffering from, or subject to, a physiological condition in need of amelioration of an inhibitor of tryptase comprising administering to the patient a therapeutically effective amount of the compound of Claim 1. The present invention is directed also to the preparation of a compound of formula I.

Description

technical field [0001] The present invention relates to disubstituted [4-(5-aminomethyl-phenyl)-piperidin-1-yl]1H-indol-3-yl-]-methanone compounds, their preparation, medicaments containing these compounds Compositions, their uses and their intermediates. Background technique [0002] Mast cell-mediated inflammatory conditions, especially in asthma, are a growing public health concern. Asthma is often characterized by progressive hyperresponsiveness of the trachea and bronchi to immune-specific allergens and general chemical or physical stimuli, leading to chronic inflammation. Leukocytes containing IgE receptors, especially mast cells and basophils, are present in the epithelium and underlying smooth muscle tissue of the bronchi. These leukocytes are initially activated by the binding of specific inhaled antigens to IgE receptors, and then release a number of chemical mediators. For example, degranulation of mast cells results in the release of proteoglycans, peroxidase,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/454C07D401/06A61P11/00A61P29/00A61P19/02A61P1/00
CPCA61K31/454A61K45/06C07D401/06A61P1/00A61P1/02A61P1/04A61P1/16A61P11/00A61P11/02A61P11/06A61P17/00A61P17/02A61P17/04A61P17/06A61P19/02A61P25/00A61P27/02A61P29/00A61P31/12A61P35/00A61P37/08A61P43/00A61P9/10A61P3/10A61K2300/00
Inventor Y-M.乔伊-斯莱德斯基C.J.加德纳梁谷岩G.B.波利P.W-K.沙姆G.T.斯托克洛萨赵志城
Owner SANOFI SA
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