Title:
非常に速い皮膚透過率を有するアリール-及びヘテロアリールプロピオン酸の正荷電水溶性プロドラッグ
Document Type and Number:
Japanese Patent JP5424880
Kind Code:
B2
Abstract:
The novel positively charged pro-drugs of aryl- and heteroarylpropionic acids in the general formula (1) 'Structure 1' and general formula (2) 'Structure 2' were designed and synthesized. The compounds of the general formula (1) 'Structure 1' and general formula (2) 'Structure 2' indicated above can be prepared from functional derivatives of naproxen, suprofen, a- methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and related compounds, (for example acid halides or mixed anhydrides), by reaction with suitable alcohols, thiols, or amines. The positively charged amino groups of these pro-drugs not only largely increases the solubility of the drugs, but also bonds to the negative charge on the phosphate head group of membranes and pushes the pro-drug into the cytosol. The results suggest that the pro-drugs diffuses through human skin -100-130 times faster than do their parent drugs. It takes 2-4 hours for naproxen, suprofen, a- methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and related compounds to reach the peak plasma level when they are taken orally, but these prodrugs only took about 40-50 minutes to reach the peak plasma level when they are taken transdermally. In plasma, more than 90% of these pro-drugs can change back to the drug in a few minutes. The prodrugs can be used medicinally in treating any NS AIAs-treatable conditions in humans or animals. The prodrugs can be administered not only orally, but also transdermally for any kind of medical treatments and avoid most of the side effects of NSAIAs, most notably GI disturbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, and gastritis. Controlled transdermal administration systems of the prodrugs enable naproxen, suprofen, a- methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and related compounds to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of NSAIAs. Another great benefit of transdermal administration of these pro-drugs is that administering medication, especially to children, will be much easier.
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Inventors:
You Chongshi
Shurina
Shurina
Application Number:
JP2009524242A
Publication Date:
February 26, 2014
Filing Date:
August 15, 2006
Export Citation:
Assignee:
Techfields Biochem Company Limited
You Chongshi
You Chongshi
International Classes:
C07C219/10; A61K31/192; A61K31/196; A61K31/341; A61K31/38; A61K31/381; A61K31/402; A61K31/403; A61K31/4035; A61K31/407; A61K31/421; A61K31/423; A61K31/436; A61P1/02; A61P1/08; A61P11/06; A61P15/00; A61P17/00; A61P19/02; A61P19/08; A61P25/02; A61P25/04; A61P25/06; A61P27/02; A61P27/06; A61P27/16; A61P29/00; A61P35/00; A61P43/00; C07C213/06; C07D207/20; C07D209/46; C07D209/86; C07D263/32; C07D263/56; C07D307/54; C07D333/24; C07D337/14; C07D487/04; C07D491/052
Domestic Patent References:
| JP64052742A | ||||
| JP2005504121A | ||||
| JP3015622B2 | ||||
| JP60054318B1 |
Attorney, Agent or Firm:
Sadao Kumakura
Nobuo Ogawa
Atsushi Hakoda
Kenji Asai
Kazuo Yamazaki
Nobuo Ogawa
Atsushi Hakoda
Kenji Asai
Kazuo Yamazaki