Dideoxycarbocyclic nucleosides

Details Dideoxycarbocyclic nucleosides Dideoxycarbocyclic nucleosides

2000-02-16

2003-03-18

Travers, Russell (Department: 1617)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

Reexamination Certificate

active

06534512

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a therapeutic method employing dideoxycarbocyclic nucleosides which exhibit antiviral activity.
BACKGROUND OF THE INVENTION
Despite intensive effort to discover drugs that may be of value in the systemic treatment of human immunodeficiency virus (HIV) infections, such infections have been singularly resistant to chemotherapy. The intracellular and intimate relation to nuclear metabolism of virus reproduction makes it difficult to destroy a virus without irreparable damage to the host cell.
The discovery of the antiviral activity of vidarabine (9-&bgr;-D-arabinoturanosyladenine monohydrate) has led to the preparation of a large number of synthetic nucleosides. To date, only one synthetic nucleoside, 3′-azido-3′-deoxythymidine has been approved for treating certain AIDS patients, but it is a palliative, not a cure.
Although AZT is specifically active against retroviruses, its use has led to side effects, including anemia, headache, confusion, anxiety, nausea and insomnia. The nucleoside analog, 2′,3′-dideoxycytidiner(DDC), exhibits an in vitro TI
50
of ca. 300 against HIV and may exhibit fewer side effects than AZT, but may also be eliminated more rapidly from the body.
The synthesis of adenine (“6-amino-purine”) nucleoside analogs in which the pentose sugar has been replaced with tris(hydroxy)-substituted cyclopentyl residues has yielded compounds with substantial cytotoxic and antiviral activity. For example, the carbocyclic analog of vidarabine, Cyclaridine, is highly active against HSV-2, but exhibits a low therapeutic index (TI
50
=10) against HIV in vitro. Likewise, the carbocyclic analog of AZT is inactive against HIV. Therefore, it is clear that the structure-activity relationships between the variously substituted carbocyclic nucleosides which have been prepared and tested remain ill-defined.
Thus, a substantial need exists for chemotherapeutic agents effective to protect mammalian cells against infection by viruses such as HSV-2, HIV, varicella-zoster, vaccinia, human cytomegalovirus (HCMV) and the like.
SUMMARY OF THE INVENTION
The present invention is directed to hydroxymethylcyclopentenyl-substituted purines and 8-aza-purines of the formula (I):
wherein Z is H, OR′ or N(R)
2
, Y is CH or N, and X is selected from the group consisting of H, N(R)
2
, SR, OR′ and halogen, wherein R is H, lower(C
1
-C
4
)alkyl, aryl or mixtures thereof, wherein R′ is H, (C
1
-C
4
)alkyl, aryl, CHO, (C
1
-C
16
)alkanoyl, or O═P(OH)
2
, and the pharmaceutically acceptable salts thereof. Preferably, X is Cl, OR′, most preferably OH; or N(R)
2
, Y is CH, R is phenyl or H, and R′ is H or acetyl. As used herein, the term “aryl” includes substituted and unsubstituted aralkyl (preferably ar(C
1
-C
4
) alkyl) moieties. Preferred aryl moieties include phenyl, tolyl, xylyl, anisyl, or phen(C
1
-C
4
)alkyl, e.g., benzyl or phenethyl. Certain of these compounds are effective antiviral and/or cytotoxic agents or are intermediates useful for the preparation thereof.
A given compound within the scope of the formula has two optically active centers, indicated by the symbol (*) in formula I, either of which can exhibit R, S or RS stereochemistry. Therefore, single resolved, optically active enantiomers and diasteriomers of the present compounds are preferred embodiments of the present invention, although partially resolved and racemic (±) mixtures are also within the scope of the invention. The four stereoisomers of the compound of formula I are depicted below:
wherein X, Y, Z and R′ are defined hereinabove. The stereoconfigurations are given using the cyclopent-2-en-4-yl-1-carbinol nomenclature.
Certain of the compounds of formula I may exist as a mixture of tautomeric forms and all such tautomers are included within the scope of the invention.
A preferred compound of the invention is the optically active enantiomer of the formula II:
wherein X, Y, 2 and R′ are as defined above and the stereochemistry at the optically active centers is as depicted. A wedged line indicates a bond extending above the plane of the cyclopentenyl ring, while a dashed line indicates a bond extending below the plane of the cyclopentenyl ring.
Although, generally compounds of formula I are not active against HSV-1, it is expected that some of them will exhibit specific antiviral activity against other viruses such as hepatitis, HSV-2. EBV, HSV, PRV, HCMV and/or HIV, as well as against other retroviruses, such as those believed to cause T-cell leukemia. Specifically, the racemic compound of formula I, wherein X is OH, Z is NH
2
, Y is CH and R′ is H (14a), strongly inhibits HIV infectivity in vitro. The TI
50
of this compound varied with the infected cell line which was used to assay for anti-HIV activity, but generally fell between 200-400, and was determined to be as high as 667 in one assay. The acetate ester (R′=Ac) of 14a was also active against HIV, giving 28% inhibition at 6 &mgr;g/ml. Compound 14a is also active against HSV-1.
The fully resolved compound of formula II, wherein X is OH, Z is NH
2
, Y is CH and R′ is H ((−)14a) is also highly active against HIV [(1′R,4′S)-2-amino-1,9-dihydro-9-[4′-hydroxymethyl-2′-cyclopenten-1-yl]-6H-purin-6-one, or (1S,4R)-4-(2-amino-6-hydroxy-9H-purin-9-yl)-2-cyclopentenylcarbinol]. Compounds of formula I wherein X is Cl or N(R)
2
, Y is CH, Z is NH
2
and R′ is H (13a and 15a, respectively) are also active against HIV, as are compounds wherein X is Cl, NH
2
or SH, Y is CH, Z is H and R′ is H (7a, 9a and 10a, respectively). Compounds 7a, 9a and 10a, as well as compounds of the formula I wherein Y=N, Z=NH
2
, X=Cl, NH
2
or OH and R′ is H (16a, 18a and 17a), are cytotoxic to cultured P-388 leukemia cells. It is believed that the antiviral activity is due to an inhibitory effect on the ability of viruses to infect normal mammalian cells. The present invention is also directed to the intermediate compound of the formula (III):
wherein Z is H or NH
2
, Z′ is H or NH
2
, and X is halogen, preferably Cl, which is useful for the preparation of the purines of the invention. Preferably, Z is NH
2
, and Z′ is H or both Z and Z′ are NH
2
. However, the compounds where X=Cl, Z=NH
2
and Z′=H or NH
2
are not active against HIV.
The (3-hydroxymethylcyclopentenyl)pyrimidine analog, 20a, is also within the scope of the present invention. Its synthesis from cyclopentene 2a is outlined in Scheme I, below.
In compounds 19a and H20a, R can be CH
3
or H. Thus, it is expected that certain of the compounds of the present invention will be useful against viral infections or virus-associated tumors, and the method of their use to inhibit viral infectivity or tumor growth in vitro or in vivo is also within the scope of the present invention.


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