Arabinosyladenine derivatives

Details Arabinosyladenine derivatives Arabinosyladenine derivatives

1999-06-24

2001-06-05

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S045000, C514S047000, C514S934000, C536S027400

Reexamination Certificate

active

06242429

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to 2-substituted arabinosyladenine derivatives having resistance to metabolism by adenosinedeaminase, pharmaceutical compositions containing the derivatives, and their use as an antiviral agent.
BACKGROUND OF THE INVENTION
Arabinosyladenine (general name: vidarabine; hereinafter referred to as “Ara-A”) is effective against DNA viruses such as herpes simplex virus (HSV), herpes zoster virus, cytomegalovirus (CMV), adenovirus, hepatitis virus and vaccinia virus. Clinically, it is mainly used as a therapeutic agent for infectious diseases associated with or caused by herpes virus. However, Ara-A is quickly metabolized by adenosinedeaminase (ADA) in the blood stream to hypoxanthine arabinoside which has weak antiviral activity. Therefore, a disadvantage of Ara-A is that its strong antiviral activity in vitro is not reflected in clinical efficacy. In addition, ADA is abundantly present in the digestive tract and, therefore, orally administered Ara-A is metabolized before being absorbed. Accordingly, oral administration of Ara-A is very difficult and, at present, only Ara-A ointment and Ara-A injections have been commercially available.
Until now, various attempts have been made for stabilization of Ara-A but each of them has the following problems and is not satisfactory:
(1) A method using Ara-A and an ADA inhibitor jointly [Sloan, B., et al,
Ann. NY. Acad. Sci.,
vol. 284, pages 60-80 (1977)].
Sloan et al discloses a method where Ara-A and an ADA inhibitor are simultaneously administered in order to stabilize Ara-A. Deoxycoformycin was used as an ADA inhibitor but an adverse reaction due to the combination was observed whereby the development was abandoned.
(2) A method for making a prodrug of Ara-A [Kotra, L. P., et al,
J. Med. Chem.,
vol. 39, pages 5202-5207 (1996)].
Kotra et al discloses a method where a compound in which an amino group at the 6-position of Ara-A is substituted with an azide group is used as a prodrug. This azide group is reduced to an amino group by cytochrome P-450 in a hepatic microsome fraction to give Ara-A in vivo. However, it is presumed that, even as compared with this reduction reaction, the metabolism by ADA is far quicker whereby it is hardly believed that the concentration of Ara-A in blood increases. Actually, although the authors describe the behavior in blood of the prodrug, 6-azido-Ara-A, they do not mention at all whether the active Ara-A itself was present in blood.
(3) A method using Ara-A derivatives resistant to metabolism by ADA [Koszalka, G. W., et al,
Antimicrobial Agents and Chemotherapy,
vol. 35, pages 1437-1443 (1991); Averett, D. R., et al,
Antimicrobial Agents and Chemotherapy,
vol. 35, pages 851-857 (1991)].
Syntheses of Ara-A analogs resistant to metabolism by ADA have been frequently conducted. Koszalka et al introduced a methylamino group, dimethylamino group or methoxyl group into the 6-position of the base and synthesized Ara-A analogs having a resistance to metabolism by ADA. This is also mentioned in Japanese Laid-Open Patent Publication Sho-63/310831. However, those compounds did not show sufficient resistance to ADA. According to a study by the present inventors, the compound of Koszalka et al (6-methylamino-9-(&bgr;-D-arabinofuranosyl)purine which is control compound C in Comparative Example 2 below and in
FIG. 3
) wherein a methylamino group is present in the 6-position, showed insufficient resistance to ADA. The resistance of the compound containing an introduced methoxyl group was weak as well. The compound which contains the dimethylamino group at the 6-position showed resistance to ADA. However, the compound is easily demethylated to a monomethyl compound in vivo and, as a result, it is also metabolized by ADA.
With regard to 2-alkyl derivatives of Ara-A, a compound where a methyl group is introduced into the 2-position (9-(&bgr;-D-arabinofuranosyl)-2-methyladenine which is control compound A in Comparative Example 1 below) is disclosed in Japanese Laid-Open Patent Publication Sho-55/45625. A compound where an ethyl group is introduced into the 2-position (9-(&bgr;-D-arabinofuranosyl)-2-ethyladenine which is control compound B in Comparative Example 1 below and in
FIG. 1
) is described in Keiko Sato et al,
Chem. Pharm. Bull.,
vol. 37, pages 1604-1608 (1989). As a result of testing by the present inventors, no strong antiviral action is obtained as shown in
FIG. 1
even when a lower alkyl group such as methyl or ethyl is introduced into the 2-position of Ara-A. In addition, those compounds are not satisfactory in terms of resistance to ADA.
The present invention solves the above-mentioned problems and provides Ara-A derivatives having resistance to metabolism by ADA and having substantial antiviral action.
SUMMARY OF THE INVENTION
The present inventors have carried out an intensive investigation for Ara-A derivatives having a high resistance to ADA and found novel 2-substituted Ara-A derivatives which exhibit substantial antiviral activity and unexpectedly superior resistance to metabolism by adenosinedeaminase (ADA). The compounds of the present invention, unlike Ara-A, provide high resistance to metabolism by ADA, without deterioration of the antiviral action of Ara-A. Accordingly, the compounds of the present invention not only show good behavior in blood with an excellent sustaining property as good as Ara-A but also are capable of being administered as an oral agent. Therefore, the compounds of the present invention have very high usefulness as therapeutic or preventive agents for diseases infected by DNA virus such as herpes simplex virus (HSV), herpes zoster virus, cytomegalovirus (CMV), adenovirus, hepatitis virus or vaccinia virus.


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Koszalka, G.W., et al.,Antimicrobial Agents and Chemotherapy, vol. 35, pp. 1437-1443 (1991).
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