Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
1999-03-01
2001-12-18
Killos, Paul J. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S533000, C560S075000
Reexamination Certificate
active
06331565
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to the new use of dicaffeoylquinic acid derivatives for treating Hepatitis B and diseases associated with retrovirus (such as HIV), the new caffeoylquinic acid derivatives and the pharmaceutical composition containing the same.
PRIOR ART
Hepatitis B is a serious worldwide disease infected by hepatitis B virus. Over 300 million individuals are chronically infected with HBV. China is a highly epidemic area of hepatitis B. In addition to causing both acute and chronic liver diseases, HBV infection is epidemically associated with a high risk of developing cirrhosis and primary hepatocellular carcinoma in human. Several types of treatment regiments have been reported for individuals with chronic HBV infection, including interferons and nucleoside analogs. However, these treatments have moderated to serious side effects, are only transiently effective in suppressing HBV, or are effective for only a small percentage of the general population of HBV-infected individuals. Even after universal implementation of neonatal vaccination there will still remain the existing carriers requiring on going treatment. There are no effective treatment for retrovirus associated disease, such as AIDS caused by HIV. Development of new effective drugs to eradicate HBV and retrovirus, such as HIV, in chronic carriers is, therefor of great potential importance.
SUMMARY OF THE INVENTION
The object of the invention is to provide a new class of drugs for treating hepatitis B and anti-retrovirus with high effective, low side action and no HBV rebound after stopping the administration of the drug.
Through widely and deep study, the inventors unexpectedly discover that dicaffeoylquinic acid derivatives and some noval caffeoylquinic acid derivatives can inhibit virus DNA replication and antigen expression of HBV and retrovirus with no rebound of HBV level after withdraw of drug. In addition, the dicaffeoylquinic acid derivatives and some new caffeoylquinic acid derivatives have potential effects on HIV. The completeness of this invention based on above discovery.
The first object of the invention relates to the new use of dicaffeoylquinic acid derivatives of formula I for treating Hepatitis B and diseases associated with retrovirus (such as HIV).
In which R
1
, R
2
and R
3
may be the same or different and represent OH or caffeoyloxy group. When R
1
is caffeoyloxy group, both R
2
and R
3
represent OH; or When R
2
is caffeoyloxy group, both R
1
and R
3
represent OH; or When R
3
is caffeoyloxy group, both R
1
and R
2
represent OH.
The second object of the invention relates to the new dicaffeoylquinic acid derivatives of formula II.
In which R
1
′, R
2
′ and R
3
′ may be the same or different and represent H, C
1-6
alkyl group.
provided that R
1
′, R
2
′ and R
3
′ can not be H at the same time,
R
1
is C
1-6
alkyl group or M that is alkali metal such as Na, K et al,
Both R
2
and R
3
represent H, C
1-6
alkyl group or CH
3
CO.
The present invention also relates to the pharmaceutical composition containing the compound of formula I which have good inhibitory effects on HBV and retrovirus such as HIV.
According to the invention, the pharmaceutical composition may contain any kinds of pharmaceutically acceptable excipients, additives or carriers.
According to the invention, the compounds of formula I and II or the pharmaceutical composition containing the same in the present invention can be used to treat the diseases relate to HBV and retrovirus, especially the diseases caused by the infection with HBV or HIV.
According to the invention, the pharmaceutical composition of the present invention can be formulated in the forms of oral or parental preparations such as tablet, capsule, granula and injection.
According to the invention, the compounds of formula I or II may be prepared by synthesis or obtained from plants such as
Inula britannic.
According to the invention, the preferred anti-HBV and retrovirus compound of the present invention is 1,5-di-O-caffeoylquinic acid as formula III.
According to the invention, 1,5-di-O-caffeoylquinic acid can be isolated from
Inula britannic.
The isolated route is shown as below:
According to the invention, 1,5-di-O-caffeoylquinic acid is also synthesized as below:
n which R
1
″ and R
2
″ may be the same or different and represent C
n
H
2n-1
OCO in which n=1-6 or R
1
″ and R
2
″ together represent one carbonyl or —CCl
2
—;
R
3
″ is H, or M that is alkali metal such as Na, K et al or alkali earth metal such as Ca, Mg, Ba, et al. or NH
4
′,
R
4
′ and R
5
′ may be the same or different and represent H, C
1-6
alkyl or C
6-10
aryl or R
4
′ and R
5
′ together with adjacent carbon atom represent C
3-7
carbocycle such as (CH
2
)
5
.
Step 1 may be performed in route 1 or route 2:
Route 1: heated at the temperature range from 60° C. to 120° C. in vacuum and inorganic or organic bases such as BaCO
3
, K
2
CO
3
, Na
2
CO
3
, NaHCO
3
may be added or not.
Route 2: solvents are added and may be any solvent provided that said solvent does not adversly affect to the reaction, such as, pyridine, triethylamine, dimethyl formamide, dimethyl sulfoxide, dichloromethane, trichloromethane, benzene, methylbenzene (toluene), acetone et al. Bases are added such as pyridine dimethylaminopyridine, triethylamine, K
2
CO
3
, Na
2
CO
3
et al. temperature range from −4° C. to 100° C.
Step 2: Reaction mixture was hydrolyzed by acid such as dilute HCl or HOAc followed by the inorganic or organic base such as NaHCO
3
, Na
2
CO
3
, KHCO
3
, K
2
CO
3
.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1
is a photograph that shows that Southern blot analysis of extracellular DNA (culture medium) of untreated (right lane) and compound A treated (15.625, 31.25, 62.5, 125 and 250 ug/ml) 22.15 cells and molecular weight marked is show on the left.
FIG. 2A
is a photograph that shows that DHBV DNA dot blot hybridization of serum sample from seven ducks before (TO), during T
7
and T
14
) and after treating with Normal Saline.
FIG. 2B
is a photograph that shows that DHBV DNA dot blot hybridization of serum sample from seven ducks before (TO), during T
7
and T
14
) and after treating with ACV at a dose of 50mg/Kg/day. ACV was administered by mouth twice daily for 14 days.
FIG. 2C
is a photograph that shows that DHBV DNA dot blot hybridization of serum sample from seven ducks before (TO), during T
7
and T
14
) and after treating with compound A at a dose of 5mg/Kg/day. Compound A was administered by mouth twice daily for 14 days.
FIG. 2D
is a photograph that shows that DHBV DNA dot blot hybridization of serum sample from seven ducks before (TO), during T
7
and T
14
) and after treating with compound A at a dose of 12.5mg/Kg/day. Compound A was administered by mouth twice daily for 14 days.
FIG. 2E
is a photograph that shows that DHBV DNA dot blot hybridization of serum sample from seven ducks before (TO), during T
7
and T
14
) and after treating with compound A at a dose 50mg/Kg/day. Compound A was administered by mouth twice daily for 14 days.
FIG. 3A
is a photograph that shows that DHBV DNA dot blot hybridization of serum sample from seven ducks before (TO), during T
5
and T
10
) and after (P
3
) treating with Normal Saline.
FIG. 3B
is a photograph that shows that DHBV DNA dot blot hybridization of serum sample from seven ducks before (TO), during T
5
and T
10
) and after treating ACV at a does of 50mg/Kg/day. ACV was administered by mouth twice daily for 14 days.
FIG. 3C
is a photograph that shows that DHBV DNA dot blot hybridization of serum sample from seven ducks before (TO), during T
5
and T
10
) and after treating with compound A at a dose of 12.5mg/Kg/day. Compound A was administered by mouth twice daily for 14 days.
FIG. 3D
is a photograph that shows that DHBV DNA dot blot hybridization of serum sample from seven ducks before (TO), during T
5
and T
10
) and after treating with compound A at a dose of 50mg/Kg/day. Compound A was admin
Dong Junxing
Mi Zhibao
Tang Zhongming
Wang Bingji
Institute of Radiation Medicine Academy of Military Medical Scie
Killos Paul J.
Ladas & Parry
LandOfFree
Dicaffeoylquinic acid for treating hepatitis B and the... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Dicaffeoylquinic acid for treating hepatitis B and the..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Dicaffeoylquinic acid for treating hepatitis B and the... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2600400