Anti-viral triaza compounds and compositions

Details Anti-viral triaza compounds and compositions Anti-viral triaza compounds and compositions

1997-08-07

2002-01-29

Travers, Russell (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S246000, C540S474000

Reexamination Certificate

active

06342492

ABSTRACT:

The invention relates to a family of new synthetic triamine compounds which can be used in pharmaceutical compositions such as antivirals.
BACKGROUND OF THE INVENTION
The number of biologically active compounds useful as antivirals is very limited. Particularly limited are anti-HIV agents. Currently approved anti-HIV drugs include nucleoside analogs such as AZT. Unfortunately, recent results of a European trial of AZT in asymptomatic HIV-infected persons showed that administration of the drug caused no difference in survival after three years. In the face of slow progress on the development of an effective AIDS vaccine, a National Task Force on AIDS Drug Development has been established to explore new approaches to AIDS chemotherapy.
It is unlikely that a cure for AIDS will be discovered because HIV integrates itself into the host's genome and the main strategy to combat the disease is to keep the HIV virus from proliferating. At least 16 steps in the HIV life cycle have been identified as possible points for therapeutic intervention, yet all of the anti-HIV drugs licensed in the U.S. so far (AZT, ddI and ddC) are nucleoside inhibitors of HIV reverse transcriptase (RT). Rapid mutation of the virus presents a key challenge to antiretroviral drug therapy and AZT-resistant strains of HIV appear in patients after prolonged treatment. Non-nucleoside RT inhibitors are currently under investigation, but it is expected that combinations of drugs operating by different mechanisms will combat viral resistance most successfully. Hence, there is an urgent search for new drugs acting at different stages in the HIV life cycle. More recently discovered anti-HIV agents include certain bicyclams and quinolines such as quinoline-4-amine. The mechanism of action of the quinoline compound is unknown, but the bicyclams are reported to be inhibitors of HIV uncoating.
Another type of compound, the triaza macrocycles, have been used primarily for metal complexation. Previously, no biological activity has been suggested for these compounds.
SUMMARY OF THE INVENTION
The present invention provides a family of triaza compounds which show antiviral properties for use against a number of viruses including HIV-1 and HIV-2.
The basic structure of the compounds is represented by formula I:
wherein
W represents a bridge carbon which is additionally bonded to at least one polar or non-polar side group substituent selected from the group consisting of double-bonded carbon, double bonded oxygen, hydroxyl, alkyl of about one to 10 carbons, alkoxy of about one to 10 carbons, aryl of about 7 to 10 carbons, a halogen, methyl halogen, methylene halide, epoxide (or oxirane), acyl, CH
2
OH and hydrogen; halogen is F, Cl, I or Br; halide is F
2
, Cl
2
, I
2
or Br
2
.
X and Y independently represent an aromatic group, an alkyl group, a sulfonyl group or a carbonyl group said aromatic group selected from the group consisting of Ar, Ar sulfonyl, Ar carboxy and Ar alkyl where Ar is an aromatic cyclic or heterocyclic ring having from five to seven members. The alkyl group which may be present for X and Y or as a substituent on Ar has from one to ten carbons. X and Y are not both an alkyl group. Preferably at least one of X or Y is an aromatic group.
Z represents a group listed for X and Y or a fused aryl moiety; said aryl moiety having from seven to ten carbons. Z may also represent hydrogen.
a and d independently represent a number from zero to 10; b and c independently represent a number from one to 10; and e represents a number from zero to three; and preferably, a+d+e≧1. Formula I represents a cyclic or acyclic structure and contains sufficient hydrogens for a stable molecule. Moieties for C
a
and C
d
can include double bonds particularly when the structure for formula I is acyclic.
In one preferred embodiment, W is ethene, X and Y are tosyl, Z is benzyl or —COR
2
, a, d, and e are one, and b and c are three.
The compounds of formula I have antiinfective activity and have a range of uses including as a pharmaceutical agent for use in the prevention and chemoprophylaxis of viral illnesses. The compounds can also be used as an antiinfective or antiseptic as a coating or additive on articles such as medical devices, contraceptives, dressings, and in blood product preparations and similar biologicals.
A method of inhibiting a virus comprises contacting the virus, a virus-containing milieu, a virus-infectable cell or a virus-infected cell with a virus-inhibiting amount of the compound of formula I.
DETAILED DESCRIPTION
The compounds are characterized as having at least three nitrogen atoms (amine sites) linked by at least two alkylene bridges or linking groups to form triamines. The alkylene bridge linking groups are preferably alkanes containing from one to ten carbons.
The triamines may be formed into a triazamacrocycle by a third alkylene bridge which is preferably alkane having from one to ten carbons connecting the two end nitrogens of the triamine compound.
The alkylene bridges linking the nitrogen atoms can additionally include aromatic or non-aromatic rings fused to the alkylene bridge. Bridges containing fused rings and linking two nitrogens of the triamine structure may be exemplified by the following:
The alkylene bridges are preferably —(CH
2
)
3
—.
The bridge carbon (designated W) of the third alkylene bridge may be functionalized with (i.e., bonded to) a side substituent which is a polar group.
Representative groups for W include
(R and R
1
are alkyl of 1-10 carbons),
(halo is F, Cl, Br or I). W may also be unfunctionalized, i.e., bonded to hydrogen. W is preferably
X and Y are independently an aromatic, alkyl, sulfonyl or carbonyl group or hydrogen. Representative aromatic groups include five or six membered rings which may have heteroatoms of nitrogen, oxygen or sulfur. The rings include, for example, phenyl, pyrrolyl, furanyl, thiophenyl, pyridyl, thiazoyl, etc. The aromatic group (Ar) for X and Y may be substituted with a hydrophilic group. Preferably the Ar is substituted with NO, NO
2
, NH
2
, NHR, NHR
2
, OH, OR, SH, SR, SOR, SO
3
R, halo, C(halogen)
3
where R is alkyl of one to 10 carbons; R is preferably alkyl of one to three carbons; R is more preferably methyl. The aromatic groups are more preferably further substituted with sulfonyl, carboxy, alkyl of one to 10 carbons or amino. Representative of groups for X and Y are
where, e.g., R is alkyl of 1 to 10 carbons, and R
2
is amino, nitro, sulfhydryl, hydroxy, alkoxy of one to three carbons, acetamino or methyl.
The alkyl groups for X and Y may be branched or unbranched and include up to ten carbons. Typical examples of alkyl groups for X and Y include methyl, ethyl, n-propyl, isopcropcyl, n-butyl, sec-butyl-, tert-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl. The alkyl groups may be in whole or in part in the form of rings such as cyclopentyl, cyclohexyl, cycloheptyl and cyclohexylmethyl. The cyclic groups may be further substituted with alkyl or aryl groups.
Preferably, X and Y both contain aromatic groups. More preferably, X and Y are both tosyl:
The groups for Z are the same as for X and Y or a fused aryl moiety. Fused rings for the Z position include naphthalene, phenanthrene, anthracene, indole, quinoline, isoquinoline, carbazole, benzimidazole and benzofuran. Z is preferably an unfused group, more preferably benezyl.
All groups for W, X, Y and Z may be further substituted with polar substituents such as NF
2
, NO, NO
2
, SH, SO
3
H, OH, and CO
2
H. These polar groups are capable of aiding solubility of the compounds.
Representative compounds include
3-Methylene-1,5-ditosyl-1,5,9-triazacyclododecane
5,9-Ditosyl-7-hydroxymethyl-1,5,9-tri-azabicyclo-[5,5,0]tridecane
5,9-Ditosyl-13-oxa-1,5,9-triazatricyclo[5,5,1
1.7
, 1
7,12
]-tetradecane
9-Benzyl-3-hydroxymethyl-1,5-ditosyl-1,5,9-triazacylododecane
9-Benzyl-3-chloromethyl-1,5-ditosyl-1,5,9-triazacyclododecane
3-Chloromethyl-1,5-ditosyl-1,5,9-triazacyclododecane
N,N-bis(3-toluenesulfonamidopropyl) toluenesulfonamide
1,5,9-Tritosyl-1

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