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Lysine based compounds

A compound and group technology, applied in the field of lysine-based compounds, can solve the problems of poor therapeutic drug concentration, patient non-compliance, inappropriate treatment results, etc., to achieve high bioavailability and improve the effect of treatment

Inactive Publication Date: 2007-04-04
AMBRILIA BIOPHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It is a deterrent that often leads to patient non-compliance and inappropriate treatment outcomes
This situation leads to suboptimal therapeutic drug concentrations, which in turn lead to the development of drug-resistant strains of HIV

Method used

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  • Lysine based compounds
  • Lysine based compounds
  • Lysine based compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0273] Example 1: (1S, 5S)-(1-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-phosphonooxy-hexylcarbamoyl}-2,2 Preparation of -diphenyl-ethyl)-carbamic acid methyl ester (PL-461)

[0274] The title compound was prepared based on Schemes 1 and 2 of the present invention.

[0275] Step A: Preparation of (3S)-3-isobutylamino-azepan-2-one (IV)

[0276] L-α-Amino-,-caprolactam (22.0 g) was dissolved in cold dichloroethane (DCM, 200 mL). Isobutyraldehyde (12.6 g) was added slowly and stirred until the exotherm disappeared (water formed on the surface). Add the cold solution to 46.5 g of crushed NaBH(OAc) 3 DCM (0.5 L) solution. To this solution was added AcOH (70 mL). The slightly cloudy mixture was stirred at 20 °C for 4 h. 500 mL of 2M NaOH solution was slowly added to the cloudy mixture, the pH was adjusted to 11 with concentrated NaOH solution, and the mixture was then stirred for another 20 min. After extraction, the DCM layer was washed with MgSO 4 Dry, filter and evap...

Embodiment 2

[0306] Example 2: (1S, 5S)-(1-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-phosphonooxy-hexylcarbamoyl}-2,2 Preparation of -diphenyl-ethyl)-methyl carbamate sodium salt (PL-462)

[0307] Add 70.7 mg of the final product of Example 1 into 1 mL of 0.1N NaOH, and dilute with 1 mL of distilled water. The solution was then lyophilized. 67.2 mg (92%) of the desired product were obtained with a purity of 95%.

[0308] 1 H NMR (CD 3 OD): δ0.72-0.83(m, 1H), 0.90(d, J=5.8, 9H), 1.26-1.38(m, 1H), 1.53-1.65(m, 1H), 1.88-2.00(m, 1H) ), 2.60-2.70(m, 1H), 2.79-2.89(m, 1H), 2.98-3.00(m, 1H), 3.00-3.08(m, 1H), 3.54(s, 3H), 3.58-3.71(m , 1H), 3.72-3.83(m, 1H), 3.84-3.95(m, 1H), 4.28(d, J=11.1, 1H), 4.91(d, J=11.0, 1H), 6.70(d, J= 7.6, 2H), 7.12-7.22(m, 2H), 7.22-7.32(m, 6H), 7.33-7.40(m, 2H), 7.50(d, J=7.7, 2H).

[0309] 31 P NMR (CD 3 OD): δ3.13

Embodiment 3

[0310] Example 3: (1S,5S)-(1-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-phosphonooxy-hexylcarbamoyl}-2-naphthalene Preparation of -2-yl-ethyl)-carbamic acid methyl ester (PL-507)

[0311] The preparation of the title compound is based on Scheme 2 of the present invention.

[0312] Step A: (1S)-(4-{[5-tert-butoxycarbonylamino-1-(diethoxyphosphoryloxymethyl)-pentyl]-isobutyl-sulfamoyl}-phenyl )-The preparation of tert-butyl carbamate (VIII)

[0313] Under an inert argon atmosphere at 0°C, 2.00 g (3.7 mmol) of (1S)-{4-[(5-tert-butoxycarbonylamino-1-hydroxymethyl-pentyl)-isobutyl-sulfamoyl] -Phenyl}-carbamic acid tert-butyl ester (VII) (Example 1, Step D) was dissolved in 0.63 mL of triethyl phosphate and 10 mL of THF. 0.63 mL (4.44 mmol) diethyl chlorophosphate was added followed by 0.25 g (6.2 mmol) NaH 60% oil dispersion in portions. The mixture was allowed to warm to room temperature and stirred for 2 h (LC-MS showed the reaction was complete after 1 h). Add 20 mL of...

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Abstract

The present invention provides lysine based compounds of the formula (I); and when the compound of formula (I) comprises an amino group, pharmaceutically acceptable ammonium salts thereof, wherein R C07C 311 / 37 C07D 207 / 44 C07D 213 / 72 C07D 215 / 38 C07D 217 / 22 C07D 241 / 44 C07D 265 / 30 C07D 233 / 88 C07D 401 / 12 C07D 403 / 12 C07D 405 / 12 A61K 31 / 18 A61K 31 / 44 A61K 31 / 4164 A61K 31 / 445 A61K 31 / 5375 A61K 31 / 47 A61K 31 / 498 0 54 17 2004 / 8 / 2 1942436 2007 / 4 / 4 000000000 Procyon Biopharma Inc. Canada B.R.Stranix V.Perron lihua yang 11038 The Patent Agency of the Chinese Council for the Promotion of International Trade (CCPIT) No.1 Waidajie, Fuxingmen, Beijing 100086 2006 / 10 / 20 PCT / CA2004 / 001440 2004 / 8 / 2 WO2006 / 012725 2006 / 2 / 9 English

Description

technical field [0001] The present invention relates to lysine based compounds which exhibit good solubility and bioavailability. More specifically, the present invention relates to lysine-based compounds having a physiologically cleavable unit whereby the compound is capable of releasing an HIV protease inhibitor upon cleavage of the unit. The compounds and pharmaceutical compositions of the present invention are particularly suitable for reducing medication burden and increasing patient compliance. Background technique [0002] Inhibitors of the HIV virus protease have not been developed until recently and their use only started in 1996. Currently, they are considered the most effective drugs against HIV infection. Unfortunately, most current protease inhibitors are relatively large, hydrophobic molecules with rather low bioavailability. A high medication burden is therefore required to achieve therapeutic doses in patients. This is a deterrent that often leads to pati...

Claims

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Application Information

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IPC IPC(8): C07C311/37C07D207/44C07D213/72C07D215/38C07D217/22C07D241/44C07D265/30C07D233/88C07D401/12C07D403/12C07D405/12A61K31/18A61K31/44A61K31/4164A61K31/445A61K31/5375A61K31/47A61K31/498
CPCC07C311/41A61K31/63A61K31/635A61K31/662C07D295/215C07F9/091C07F9/6533A61P31/18
Inventor B·R·斯特拉尼克斯V·佩龙
Owner AMBRILIA BIOPHARMA INC
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