Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-06-26
2004-03-09
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S569000, C540S572000, C540S574000
Reexamination Certificate
active
06703387
ABSTRACT:
BACKGROUND OF THE INVENTION
Human papillomaviruses (HPV) are non-enveloped DNA viruses that induce hyperproliferative lesions of cutaneous and mucosal epithelia (warts).(Ref: P Howley—In Fields Virology 2
nd
Edn. Chap. 58 pp1625-1676 eds Fields et al Raven Press NY 1990) Genital HPV infection is one of the most common sexually transmitted diseases. (Ref Maw RD, Reitas M and Roy M, Int J STD+AIDS 9, 571-578, (1998)). It is estimated that visible genital warts are present in 1% of sexually active adults in the USA and that at least 15% have subclinical infection. (Koutsky L., Am. J. Med. 102, 3-8 (1997)). Over 90% of benign external warts (condyloma acuminata) are caused by HPV genotypes 6 and 11 (Handsfield H. H. Am. J. Med. 102, 16-27 (1997)).
E1 Helicase is the only known HPV enzyme and is essential for viral DNA replication. The E1 protein has been shown to possess ATPase and ATP-dependent DNA helicase catalytic activities. It is proposed to function as a hexameric helicase and sequence homology classifies it as a member of helicase superfamily III (other members: SV40 TAg, parvovirus NS1). Inhibition of the ATPase or helicase functions of this enzyme would be predicted to result in inhibition of HPV DNA replication.
The object of the present invention is to provide novel compounds which are potent inhibitors of the ATPase activity of the helicase enzyme and which accordingly show a potential to be efficacious as antiviral drugs.
SUMMARY OF THE INVENTION
The present invention comprises novel benzodiazepine derivatives of the formula
The novel compounds are inhibitors of the human papilloma virus (HPV) E1 helicase enzyme and can therefore be used as therapeutic agents for HPV mediated diseases.
DETAILED DESCRIPTION OF THE INVENTION
The present invention comprises novel compounds of the formula:
wherein
R
1
is H, lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, lower alkyl carbonyl, aryl carbonyl, lower alkyl amino carbonyl, aryl amino carbonyl, lower alkoxy carbonyl, aryloxy carbonyl,
R
2a
, R
2b
independently are H or lower alkyl or
R
2a
and R
2b
together are oxo,
R
1
and R
2a
or R
2b
together with the nitrogen and the carbon atom to which they are attached form aheterocycle;
R
3a
, R
3b
independently are H or lower alkyl
R
4
and R
5
together with the two carbon atoms to which they are attached form aryl or a heterocycle,
R
6
and R
7
is H or lower alkyl and
R
8
is aryl or heterocyclyl.
The term “lower” used in combination with alkyl and alkoxy defines an optionally substituted straight chained or branched alkyl chain carrying 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. The term “lower” used in combination with alkenyl and alkynyl defines an optionally substituted straight chained or branched alkenyl or alkynyl chain carrying 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms.
Lower alkyl in R
1
,R
2a
, R
2b
, R
3a
, R
3b
, R
6
and R
7
accordingly preferably stands for methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and tert.-butyl.
Lower alkoxy in R
1
preferably stands for methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy and tert.-butoxy.
Lower alkenyl in R
1
accordingly preferably is vinyl, 1-propenyl, 2-propenyl, i-propenyl and butenyl and its isomers.
Lower alkynyl in R
1
accordingly preferably is ethynyl, propynyl and its isomers and butynyl and its isomers.
Preferred meaning for R
1
is methyl.
Preferred meaning for R
2a
, R
2b
, R
3a
, R
3b
, R
6
and R
7
is hydrogen.
Suitable substituents of an alkyl chain can be selected from one or more of aryl, heterocyclyl, carboxyl, cyano, alkoxy, cycloalkyl oxy, aryl oxy, heterocyclyl oxy, hydroxyl, alkyl carbonyl, cycloalkyl carbonyl, aryl carbonyl, heterocyclyl carbonyl, alkoxy carbonyl, cycloalkyl oxy carbonyl, aryl oxy carbonyl, heterocyclyl oxy carbonyl, amino carbonyl, alkyl amino carbonyl, dialkyl amino carbonyl, cycloalkyl amino carbonyl, aryl amino carbonyl, heterocyclyl amino carbonyl, amino, alkyl amino, dialkyl amino, alkenyl amino, alkynyl amino, cycloalkyl amino, aryl amino, heterocyclyl amino, alkyl carbonyl amino, dialkyl carbonyl amino, cycloalkyl carbonyl amino, aryl carbonyl amino, heterocyclyl carbonyl amino, alkoxy carbonyl amino, cycloalkyl oxy carbonyl amino, aryloxy carbonyl amino, heterocylyl oxy carbonyl amino, alkyl amino carbonyl amino, dialkyl amino carbonyl amino, cycloalkyl amino carbonyl amino, aryl amino carbonyl amino, heterocyclyl amino carbonyl amino alkyl sulfonyl amino, cycloalkyl sulfonyl amino, aryl sulfonyl amino, heterocyclyl sulfonyl amino, nitro, alkyl sulfonyl, cycloalkyl sulfonyl, aryl sulfonyl, heterocyclyl sulfonyl, thio, alkyl thio, cycloalkyl thio, aryl thio, heterocyclyl thio or halogen.
In all cases above where there are NH groups, the free hydrogen may also be substituted, preferably with lower alkyl. Examples are alkyl carbonyl (lower alkyl) amino, cycloalkyl (lower alkyl) amino carbonyl or alkoxy carbonyl (lower alkyl) amino.
The term cycloalkyl has the meaning of an optionally substituted cycloalkyl group containing 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl or adamantyl which can also be benz-fused to an optionally substituted saturated, partially unsaturated or aromatic monocyclic, bicyclic or tricyclic heterocycle or carbocycle, e.g. to phenyl.
The term aryl denotes optionally substituted phenyl and naphthyl, both optionally benz-fused to an optionally substituted saturated, partially unsaturated or aromatic monocyclic, bicyclic or tricyclic heterocycle or carbocycle e.g. to cyclohexyl or cyclopentyl.
The term heterocyclyl stands for an optionally substituted saturated, partially unsaturated or aromatic monocyclic, bicyclic or tricyclic heterocycle which contains one or more hetero atoms selected from nitrogen, oxygen and sulfur which can also be benz-fused to an optionally substituted saturated, partially unsaturated or aromatic monocyclic, bicyclic or tricyclic carbocycle or heterocycle.
Preferred heterocycles are oxazolyl, isoxazolyl, furyl, tetrahydrofuryl, 1,3-dioxolanyl, dihydropyranyl, thienyl, pyrazinyl, isothiazolyl isoquinolinyl, indolyl, indazolyl, quinolinyl, dihydrooxazolyl, pyrimidinyl, benzofuranyl, tetrazolyl, pyrrolidinonyl, (N-oxide)-pyridinyl, pyrrol, triazolyl e.g. 1,2,4-triazolyl, pyrazolyl, benzotriazolyl, priperidinyl, morpholinyl, thiazolyl, pyridinyl, dihydrothiazolyl, imidazolidinyl, pyrazolinyl, benzothienyl, piperazinyl, imidazolyl, thia diazolyl e.g. 1,2,3-thiadiazolyl, and benzothiazolyl.
Suitable substituents for cycloalkyl, aryl, heterocyclyl can be selected from those named for alkyl, in addition however lower alkyl, lower alkenyl and lower alkynyl are substituents to be added to the selection.
The term halogen stands for fluorine, chlorine, bromine and iodine.
R
4
and R
5
together with the two carbon atoms to which they are attached preferably form optionally substituted aryl, more preferably form optionally substituted phenyl.
R
8
preferably stands for optionally substituted aryl, more preferably for optionally substituted phenyl.
Any functional (i.e. reactive) group present in a side-chain may be protected, with the protecting group being a group which is known per se, for example, as described in “Protective Groups in Organic Synthesis”, 2
nd
Ed., T. W. Greene and P. G. M. Wuts, John Wiley & Sons, New York, N.Y., 1991. For example, an amino group can be protected by a tert.-butoxycarbonyl (BOC), formyl, trityl, benzyloxycarbonyl (Z), 9-fluorenylmethyloxcarbonyl (FMOC), trifluoroacetyl, 2-(biphenylyl)isopropoxycarbonyl or isobornyloxycarbonyl group or in the form of a phthalimido group; or a hydroxyl group can be protected by a tert.butyldimethylsilyl, tetrahydropyranyl, 4-methoxybenzyl, or benzyl; or a carboxyl group can be protected in the form of an ester, for example as a methyl or tert.butyl ester. The protecting group may be retained in the final compound or optionally be removed by techniques known in the art.
The compounds of this invention may contain one or more asymmetr
Hurst David N.
Jones Philip Stephen
Parkes Kevin Edward Burdon
Parratt Martin John
Wilson Francis Xavier
Hoffmann-La Roche Inc.
Johnston George W.
Patel Sudhaker B.
Shah Mukund J.
Tramaloni Dennis P.
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