The United States of America As Represented by the Department of Health

The United States of America As Represented by the Secretary of

The United States of America

The Government of the United States of America, As Represented by the

Government of the United States

Institute of Molecular & Cell Biology

United States Government As Represented by the Secretary of the Dept. of

John S Driscoll

Victor E Marquez

Alberto Haces

James A Kelley

Christopher K-h Tseng

Hiroaki Mitsuya

A Hameed Khan

Feng-te Chou

David G Johns

Mu-Ill Lim

Robert I Glazer

Magbool A Siddiqui

Theodore Breitman

Ronald J Wysocki, Jr

Maqbool A Siddiqui

Joseph J Barchi, Jr

Yin Hwee Tan

Christopher K Tseng

Sim Mui Mui

John A Beisler

Mohamed M Abbasi

Geoffrey Peng

Paul S Liu

Harry Ford, Jr

Chong-Ho Kim

Joseph E Tomaszewski

Flavivirus, rhabdovirus and paramyxovirus infections may be treated by administering an inhibitor of the enzyme dihydroorotate dehydrogenase such as 6-fluoro-2-(2'-fluoro-1,1&#x2032;-biphenyl-4-yl)-3-methyl-4-quinolinearcarboxylic acid sodium salt (Brequinar). A synergistic effect can be obtained if an interferon such as interferon &#x3b1;2, interferon &#x3b1;8 or interferon &#x3b2;, or an inhibitor of a second enzyme selected from inosine monophosphate dehydrogenase, guanosine monophosphate synthetase, cytidine triphosphate synthetase and S-adenosylhomocysteine hydrolase, is also administered.

Dihydroorotate dehydrogenase inhibitors for the treatment of viral-mediated diseases

A method of preparing a 2'-fluoro compound of the formula ##STR1## where B is selected from the group consisting of purines and pyrimidines, both of which may be substituted, comprises reacting a compound of the formula II(a) or II(b) ##STR2## where R and R' are as defined in the specification with an acid halide under conditions effective to obtain a halide of the formula ##STR3## where X is a halogen. A silane of the formula B-Si (R').sub.3 where R' is as defined in the specification, is added to this product (III) under conditions effective to obtain a compound of the formula (IV) ##STR4## The compound of formula (IV) is reacted with a reagent selected from the group consisting of ammonia, BCl.sub.3 and ((C.sub.1 -C.sub.10)alkyl).sub.4 NF, under conditions effective to obtain the compound of formula (I). The compounds of formula (I) resulting from these methods exhibit anti-HIV activities and are useful for therapy against the HIV virus.

2'-Fluorofuranosyl derivatives and methods for preparing

Methods of treating a human infected with human immunodeficiency virus (HIV), such as a human with AIDS, with the purina nucleotides 2',3'-dideoxy-2'-beta-fluoroadenosine (FddA) and 2',3'-dideoxy-2'-beta-fluoroinosine (FddI) are disclosed. These nucleotides are stable in an acid environment and thus can be used for oral administration. Methods of inhibiting human immunodeficiency virus replication in a human T cell using these purina nucleotides are also disclosed.

2',3'-dideoxy-2'-fluoro-purine nucleosides and methods for using same

The present invention provides a novel synthetic route to a key precursor, i.e., an (S,S)-.alpha.-fluoro-2,2-dimethyl-1,3-dioxolane-4-propanoic acid ester useful in the preparation of FddA and FddC. The instant diastereoselective process utilizes a novel intermediate which contains a chiral auxiliary. The chiral auxiliary can be any chiral auxiliary moiety such as for example an auxiliary containing a substituted oxazolidinone group. The intermediate containing the chiral auxiliary is fluorinated utilizing a fluorination method applied for the first time in the synthesis of fluorinated sugars to give a fluorinated intermediate which after removal of the chiral group provides the desired key intermediate. In summary, in the instant process, a fluorine is introduced diastereoselectively into an intermediate via the reaction of a chiral enolate with an electrophilic fluorinating agent and the intermediate which is fluorinated is derived from mannitol.

Diastereoselective process leading to a key intermediate for the

Purine nucleosides active against human immunodeficiency virus which are substituted at the 2'-position by a strong electronegative group such as fluorine are stable in an acid environment and thus can be used for oral administration.

Acid stable purine dideoxynucleosides

The present invention relates, in general, to prodrugs. In particular, the present invention relates to lipophilic, aminohydrolase-activated, anti-viral nucleoside prodrug compounds, pharmaceutical compositions containing these compounds, and methods of using these compounds.

Lipophilic, aminohydrolase-activated prodrugs

A compound has the formula ##STR1## wherein R is selected from the group consisting of (C.sub.7 -C.sub.20)aroyl, (C.sub.6 -C.sub.20)aryl, aralkyl and alkylaryl, and (C.sub.1 -C.sub.10)alkyl-di(C.sub.6 -C.sub.20)aryl Si, R' is selected from the group consisting of (C.sub.1 -C.sub.10)alkyl, (C.sub.7 -C.sub.20)aroyl and (C.sub.2 -C.sub.12)acyl, all of which may be further substituted with O, S, N or alkyl, and R'' is selected from the group consisting of halogen, (C.sub.1 -C.sub.10)alkoxy, (C.sub.1 -C.sub.10)acyloxy, O-methane-sulfonyl and O-p-toluenesulfonyl. A composition of matter comprises 0.001 to 99.999 wt % of the above compound.

2'-fluorofuranosyl derivatives and novel method of preparing

Several analogues of hexamethylene bis[acetamide] were found to be effective differentiating agents. The most effective of these compounds was 3,3'-(1,6-hexandiyl)bis[5,5-dimethyl-2,4-imidazolinedione].

Chemical differentiating agents

Cyclopentenyl pyrimidine compounds have potent anti-viral, anti-tumor and differentiating activity. Of these compounds, cyclopentenyl cytosine has proved to be particularly effective in a variety of tumors, as well as having good antiviral activity and potent differentiating properties.

Antiviral and anticancer cyclopentenyl cytosine

The new compound 3-deazaneplanocin A has been discovered to have potent anti-viral, anti-tumor activity and differentiating activity. A simple method for preparing 3-deazaneplanocin A has been developed involving nucleophilic substitution, which method can also be used to prepare a great variety of carbocyclic nucleosides.

3-deazaneplanocin, intermediates for it, and antiviral composition and

5-substituted 2',3'-dideoxycytidine compounds and their monophosphates are disclosed which have been found to have potent activity against retroviruses. The 5-fluoro-and 5-aza-substituted 2',3'-dideoycytidine compounds have been found to be effective against HTLV-III/LAV virus.

5-substituted-2',3'-dideoxycytidine compounds with anti-HTLV-III activity

The use of aziridinyl quinones as antitumor agents is disclosed. A compound which has been found to be particularly effective is the compound 2,5-diaziridinyl-3,6-bis (carboethoxyamino)-1,4-benzoquinone. Treatment is described in connection with various forms of leukemia, for example, as well as B16 melanoma, Lewis lung carcinoma, and the ependymoblastoma brain tumor system.

Aziridinyl quinone antitumor agents

Seven-membered heterocyclic nucleosides used to inhibit the deamination enzyme responsible for the inactivation of arabinosylcytosine (ara--C). Preferred nucleosides containing a seven-member aglycone are as follows: ##STR1## Preferred aglycones are as follows: ##STR2## Active components utilized against pyrimidine deaminases from mammalian tissues (mouse kidney and human liver) showed optimum advantage when compared with tetrahydrouridine (THU).

Seven-membered ring compounds as inhibitors of cytidine deaminase

The use of aziridinyl quinones as antitumor agents against transplanted tumors in mice is disclosed. A compound which has been found to be particularly effective is the compound 2,5-diaziridinyl-3,6-bis (carboethoxyamino)-1,4-benzoquinone. Treatment is described in connection with several transplanted mouse tumor test systems including various forms of leukemia, for example, as well as B16 melanoma, Lewis lung carcinoma, and the ependymoblastoma brain tumor system.

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Rockville, MD, United States of America

John S Driscoll