Title:
皮膚浸透率の非常に高い1H-イミダゾ[4,5-c]キノリン-4-アミン及び関連化合物の正に荷電した水溶性プロドラッグ
Document Type and Number:
Japanese Patent JP2010516802
Kind Code:
A
Abstract:
The novel positively charged pro-drugs of 1H-imidazo[4, 5-c]quinolin-4-amines and related compounds in the general formula (1) 'Structure 1' or formula (2) 'Structure 2' were designed and synthesized. The compounds of the general formula (1) 'Structure 1' or formula (2) 'Structure 2' indicated above can be prepared from 1H-imidazo[4, 5-c]quinolin-4-amines and related compounds, by reaction with suitable acetic anhydride or acetic chloride. The positively charged amino groups of these pro-drugs not only largely increases the solubility of the drugs in water, but also bonds to the negative charge on the phosphate head group of membranes. This bonding will disturb the membrane a little bit and may make some room for the lipophilic portion of the prodrug. When the molecules of membrane move, the membrane may 'crack' a little bit due to the bonding of the prodrug. This will let the prodrug insert into the membrane. At pH 7.4, only about 99% of the amino group is protonated. When the amino group is not protonated, the bonding between the amino group of the prodrug and the phosphate head group of the membrane will disassociate, and the prodrug will enter the membrane completely. When the amino group of the prodrug flips to the other side of the membrane and thus becomes protonated, then the prodrug is pulled into the cytosol, a semi-liquid concentrated aqueous solution or suspension. The results suggest that the pro-drugs diffuse through human skin -25 times faster than do 1H-imidazo[4, 5-c]quinolin-4-amines and related compounds. In plasma, more than 90% of these pro-drugs can change back to the parent drugs in a few minutes. The prodrugs can be used medicinally in treating any 1H-imidazo[4,5-c]quinolin-4-amines and related compounds-treatable conditions in humans or animals. The prodrugs can be administered transdermally for any kind of medical treatments and avoid most of the side effects of 1H-imidazo[4,5-c] quinolin-4-amines and related compounds. Controlled transdermal administration systems of the prodrug enables 1H-imidazo[4, 5-c]quinolin-4-amines and related compounds to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of 1H-imidazo[4, 5-c]quinolin-4-amines and related compounds.
Inventors:
You Chongshi
Application Number:
JP2009547772A
Publication Date:
May 20, 2010
Filing Date:
January 31, 2007
Export Citation:
Assignee:
You Chongshi
International Classes:
C07D471/04; A61K9/08; A61K9/107; A61K9/12; A61K9/16; A61K9/70; A61K31/4745; A61K45/00; A61P7/04; A61P11/00; A61P17/04; A61P17/06; A61P25/00; A61P31/16; A61P31/18; A61P31/20; A61P35/00; A61P43/00
Domestic Patent References:
| JP2007532572A | 2007-11-15 | |||
| JP2007532572A | 2007-11-15 |
Foreign References:
| WO2007149802A2 | 2007-12-27 | |||
| US4689338A | 1987-08-25 | |||
| US4698348A | 1987-10-06 | |||
| WO2005025583A2 | 2005-03-24 | |||
| WO1993025197A1 | 1993-12-23 | |||
| WO2007149802A2 | 2007-12-27 | |||
| US4689338A | 1987-08-25 | |||
| US4698348A | 1987-10-06 |
Other References:
JPN6012031396; Ｓｉｌｖｅｒｍａｎ， Ｒ．Ｂ．: Ｔｈｅ Ｏｒｇａｎｉｃ Ｃｈｅｍｉｓｔｒｙ ｏｆ Ｄｒｕｇ Ｄｅｓｉｇｎ ａｎｄ Ｄｒｕｇ Ａｃｔｉｏｎ , 1992, ３５５-３６１, Ａｃａｄｅｍｉｃ Ｐｒｅｓｓ Ｉｎｃ．
Attorney, Agent or Firm:
Sadao Kumakura
Nobuo Ogawa
Atsushi Hakoda
Kenji Asai
Kazuo Yamazaki
Shimura
Nobuo Ogawa
Atsushi Hakoda
Kenji Asai
Kazuo Yamazaki
Shimura