Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Patent
1995-11-17
1998-10-06
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
544244, 544265, 558187, 558189, 514262, A61K 31675, C07F 96512
Patent
active
058176470
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/US94/01837 Feb. 25, 1994.
The present invention comprises unsaturated phosphonate derivatives of certain purines or pyrimidines useful as anti-viral agents, to methods and intermediates useful for their preparation and to their end-use application as antiviral agents effective against DNA viruses (herpes viruses 1 and 2, cytomegalovirus, varicella-zoster virus, Epstein-Barr virus), retroviruses (human immunodeficiency viruses 1 and 2 and visna virus) and against viruses involved in tumor formation.
BACKGROUND OF THE INVENTION
Certain derivatives of purine or pyrimidine bases have shown antiviral and antitumor activity. For example, see EP 0 173,624; EP 0 253,412; EP 0 353,955; WO 92/01698; EP 0 481,214; and J. Org. Chem. 57: 2320-2327 (1992). The compounds of the present invention represent novel compounds derived from purine and pyrimidine bases.
SUMMARY OF THE PRESENT INVENTION
More specifically this invention relates to novel compounds of Formula I and Formula II: ##STR1## the stereoisomeric forms, tautomeric forms and the pharmaceutically acceptable salts thereof, wherein OCH.sub.2 ; ##STR2## wherein each of R.sub.1 and R.sub.2 are independently H, F or CH.sub.2 OH; T is nothing, T' or T", wherein OH), or CH.sub.2 CH(OH), R.sub.4 is OH then the other is not --O--CH(R.sub.6)--O--C(O)R.sub.5, wherein R.sub.5 and R.sub.5 ' are each independently C.sub.1-15 alkyl or benzyl, and R.sub.6 is H or C.sub.1-10 alkyl, is CH.sub.2, then X.sub.1 is not NH.sub.2 and X.sub.2 is not OH simultaneously; and
The present invention also comprises using the compounds of Formula I and Formula II to prepare a pharmaceutical composition for treating viral infections.
DETAILED DESCRIPTION OF THE PRESENT INVENTION
The compounds of the present invention are purine derivatives (Formula I) or pyrimidine derivatives (Formula II), herein referred to as nucleic bases (dotted line representing the attachment to the rest of the molecule): ##STR3## having a phosphonate moiety. Linking the phosphonate moiety to the purine or pyrimidine derivative are moieties T, W and Z groups. An example of the attachment of these moieties to the rest of the molecule follows where T is T" and is CH.dbd.CH--CH(CH.sub.2 OH), W is W.sub.a wherein R.sub.1 and R.sub.2 are each H, and Z is CH.sub.2 O: ##STR4##
The following combinations, being smaller molecules of the present invention, are preferred.
Other preferred compounds are when T is T', and more preferably T' is CH.dbd.CH; when T is T", and more preferably T" is CH.sub.2 OCH.sub.2 ; when W is W.sub.a, W.sub.c or W.sub.d ; when each of R.sub.1 and R.sub.2 is H; and/or Z is CH.sub.2, CH.sub.2 CH.sub.2 or CH.sub.2 O. Formula I is preferred over Formula II. Preferred pyrimidine type bases are cytosine, uracil, and thymine. Preferred purine bases are 2,6-diaminopurine (DAP), guanine and adenine.
As used herein the proviso "when T is CH.dbd.CH or CH.sub.2 CH.sub.2, W is W.sub.c and Z is CH.sub.2 then X.sub.1 is not NH.sub.2 and X.sub.2 is not OH simultaneously" is meant to exclude compounds from the claims where guanine (X.sub.1 =NH.sub.2 and X.sub.2 =OH simultaneously) is the base. This proviso excludes two compounds where guanine is the base: when (1) T is CH.dbd.CH, W is W.sub.c and Z is CH.sub.2, and (2) T is CH.sub.2 CH.sub.2, W is W.sub.c and Z is CH.sub.2.
The term C.sub.1-10 alkyl or C.sub.1-15 alkyl means respectively an alkyl moiety having between 1 to 10 carbon atoms or 1 to 15 carbon atoms. The alkyl moiety may be straight-chain or branched, e.g., tert-butyl. For the C.sub.1-15 alkyl moiety, C.sub.1-10 alkyl is preferred and C.sub.1-6 more preferred and C.sub.1-3 most preferred. For the C.sub.1-10 alkyl moiety, C.sub.1-6 is preferred and C.sub.1-3 most preferred.
The term "pharmaceutically acceptable salts" means both acid addition salts and metal and amine salts which are known to be non-toxic and useful derivatives in the preparation of pharmaceutical formulations suitable for end-use applications.
Pharmaceutically acceptable acid addition salts include
REFERENCES:
patent: 5032592 (1991-07-01), Hughes et al.
patent: 5055458 (1991-10-01), Bailey et al.
patent: 5166198 (1992-11-01), Harnden et al.
patent: 5532225 (1996-07-01), Reist et al.
J. Org. Chem (1992) vol. 57, No. 8, pp. 2320-2327--Sreenivasulu Megati et al. "Unsaturated phosphonates as acyclic nucleotide analogues. Anomalous Michaelis-Arbuzov and Michaelis-Becker reactions with multiple bond".
J. Med. Chem. (1993) vol. 36, No. 10, pp. 1343-1355--M.R. Harden et al. "Novel acyclonucleotides: synthesis and antiviral activity of alkenylphosphonic acid derivatives of purines and a pyrimidine".
Casara Patrick
Halazy Serge
Nave Jean-Fran.cedilla.ois
Merrell Pharmaceuticals Inc.
Nelligan Mark C.
Shah Mukund J.
Sripada Pavanaram K.
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