Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-12-15
2002-04-23
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S337000, C514S469000, C544S125000, C546S284100, C549S467000
Reexamination Certificate
active
06376491
ABSTRACT:
BACKGROUND OF THE INVENTION
N-myristoyltransferase (hereinafter referred to as NMT) is an enzyme that transfers cellular fatty acid myristate from myristoyl CoA to the N-terminal glycine of eukaryotic cellular proteins. N-myristoylation of several G-proteins, Gpa1, Arf1, Arf2 and Vps15, which are essential for fungal growth, have been reported to be indispensable for their function in
Saccharomyces cerevisiae
(K. J. Lodge el al., Proc. Natl. Acad. Sci., Vol. 91, PP. 12008-12012, 1994; D. R. Johnson et al., Annu. Rev. Biochem., Vol. 63, PP. 869-914, 1994; Stearns T. et al., Mol. Cell Biol., Vol.10, PP. 6690-6699, 1990; P. K. Harman et al., Cell, Vol. 64, PP. 425-437, 1991). Genetic studies have also demonstrated that this enzyme is essential for the viability of the fungi including medically important pathogenic fungi. For example, the essentiality of the enzyme in
S. cerevisiae
has been reported by Robert J. Duronio et al. (Proc. Natl. Acad. Sci., Vol. 89, pp. 4129-4133, 1992), the essentiality in
Candida albicans
has been reported by Robin A. Weiberg et al. (Molecular Microbiology, Vol. 16, PP. 241-250, 1995), and the essentiality in
Cryptococcus neoformans
has been reported by K. J. Lodge et al. (Proc. Natl. Acad. Sci., Vol. 91, pp. 12008-12012, 1994). Therefore, NMT has been believed to be a target for the development of fungicidal drugs.
SUMMARY OF THE INVENTION
In accordance with the present invention it has been found that the novel bicyclic compounds show NMT inhibitory activity and antifungal activity. The present invention relates to these novel bicyclic compounds having NMT inhibitory activity and antifungal activity, processes for producing the same, the use in the medical therapy of said compounds and pharmaceutical compositions containing said compounds.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to novel bicyclic compounds of the formula [I],
wherein
R
1
is hydrogen, an unsubstituted or substituted heterocyclic ring,
R
2
is hydrogen, unsubstituted or substituted lower alkyl, aralkyl, cycloalkyl or cycloalkylalkyl;
R
3
, R
4
and R
5
are independently hydrogen or halogen;
R
6
and R
7
are independently hydrogen, unsubstituted or substituted lower alkyl, an aromatic ring or aliphatic ring which may contain heteroatom(s); or R
6
and R
7
form an aliphatic ring which may contain further heteroatom(s) together with the adjacent Q
2
, N and Q
3
; or Q
1
and R
6
form an aliphatic ring which may contain further heteroatom(s) together with the adjacent N and Q
2
;
R
8
, R
9
and R
10
are independently hydrogen, unsubstituted or substituted lower alkyl, aralkyl, cycloalkyl, cycloalkylalkyl, an aromatic ring or aliphatic ring which may contain heteroatom(s); or R
9
and R
10
form an aliphatic ring which may contain further heteroatom(s) together with the adjacent nitrogen;
Q
1
is unsubstituted or substituted lower alkylene other than unsubstituted or substituted methylene;
Q
2
and Q
3
are each independently a single bond, unsubstituted or substituted lower alkylene;
Q
4
is a single bond, carbonyl, oxime, oxime O-ether which has a substituted or unsubstituted lower alkyl, lower alkenyl, aralkyl or aryl radical on the oxygen atom, or unsubstituted or substituted lower alkylene;
Q5 is a single bond or carbonyl; and
x is an integer of0 to 2;
with the proviso that when R
1
is —COOC
2
H
5
, then
and pharmaceutically acceptable salts thereof.
Unless otherwise indicated, the following definitions are set forth to illustrate and defined the meaning and scope of the various terms used to describe the invention herein.
In this specification the term “heterocyclic ring” is used to mean a radical of a 3 to 10 membered ring containing one or more heteroatom(s), such as N, S and O.
The term “lower” is used to mean a radical consisting of 1 to 5, preferably 1 to 4 carbon atom(s), unless otherwise indicated.
The term “alkyl” refers to a branched or straight chain monovalent saturated aliphatic hydrocarbon radical of 1 to 5, preferably 1 to 4 carbon atom(s).
The term “alkenyl” refers to a branched or straight chain monovalent unsaturated aliphatic hydrocarbon radical of 3 to 5 carbon atom(s).
The term “aralkyl” refers to a branched or straight chain monovalent saturated aliphatic hydrocarbon radical of 1 to 5, preferably 1 to 3 carbon atom(s) having a monovalent carbocyclic aromatic radical such as phenyl, naphthyl optionally mono-, di-, tri- or tetra-substituted, independently, with lower alkyl, trifluoromethyl, halogen and the like.
The term “cycloalkyl” refers to a monovalent carbocyclic radical of 3 to 10 carbon atom(s), preferably 3 to 6 carbon atoms.
The term “cycloalkylalkyl” refers to a branched or straight chain monovalent saturated aliphatic carbon radical of 1 to 5, preferably 1 to 4 carbon atom(s) having a monovalent carbocyclic radical of 3 to 10 carbon atom(s), preferably 3 to 6 carbon atoms.
The term “aromatic ring” refers to a monovalent 5 to 10 membered aromatic hydrocarbon radical, i.e. “aryl”, or heteroaromatic radical.
The term “aliphatic ring” refers to a monovalent carbocyclic radical of 3 to 10 carbon atom(s), preferably 3 to 6 carbon atoms.
The term “heteroatom” refers to N, O and S.
The term “lower alkylene” refers to a branched or straight chain aliphatic hydrocarbon radical of 1 to 5, preferably 1 to 4 carbon atom(s).
The term “halogen” refers to fluoro, chloro, bromo and iodo.
The term “acyl” refers to a monovalent carbonyl radical having a hydrogen, heterocyclic ring defined above, lower alkyl defined above, aralkyl defined above, cycloalkyl defined above, cycloalkylalkyl defined above or aromatic ring defined above.
The term “acyloxy” refers to a monovalent oxy-radical having an acyl radical defined above.
The term “alkoxy” refers to the group —O—R′, where R′ is an alkyl.
The present invention also relates to the use of the compounds of formula [I] in the prophylaxis and/or treatment of mycoses. Furthermore, the present invention relates to a pharmaceutical composition comprising a compound of formula [I] as an active ingredient and a pharmaceutically acceptable carrier.
The respective groups in the formula [I], which are defined above, are explained in more detail as follows:
In a preferred embodiment, R
1
is hydrogen, unsubstituted or substituted heterocyclic ring,
wherein R
8
, R
9
and R
10
are independently hydrogen, unsubstituted or substituted lower alkyl, aralkyl, cycloalkyl, cycloalkylalkyl or an aromatic ring or aliphatic ring which may contain heteroatom(s); or R
9
and R
10
form an aliphatic ring which may contain further heteroatom(s) together with the adjacent nitrogen; and Q
4
is a single bond, carbonyl, oxime, oxime O-ether which has a substituted or unsubstituted lower alkyl, lower alkenyl, aralkyl or aryl radical on the oxygen atom, or unsubstituted or substituted lower alkylene; Q
5
is a single bond or carbonyl; and x is an integer of 0 to 2.
In the above definitions of R
1
, the term “heterocyclic ring” means a 3 to 10 membered ring containing one or more heteroatom(s) such as N, S and O, preferably 1 to 4. More preferably, “unsubstituted heterocyclic ring” means oxazolyl, thiazolyl, 4,5-dihydro-oxazolyl, 4,5-dihydro-thiazolyl, furyl, pyrrolyl, thienyl, imidazolyl, triazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, triazinyl, oxadiazolyl, thiadiazolyl and the like, more preferably oxazolyl, thiazolyl, 4,5-dihydro-oxazolyl and 4,5-dihydro-thiazolyl.
“Substituted heterocyclic ring” means a heterocyclic ring as defined above having one or more substituents such as F, Cl, Br, I, hydroxy, hydroxymethyl, nitro, cyano and unsubstituted or substituted amino, lower alkoxycarbonyl, lower alkyl, lower alkoxy, cycloalkylalkyl, aralkyl, carbamoyl, acyl, acyloxy, (heterocyclic ring)-carbonyl and heterocyclic ring. The preferred heterocyclic ring substituents are unsubstituted or substituted lower alkyl, lower alkoxy, lower alkoxycarbonyl, (lower alkyl)carbamoyl, arylcarbamoyl, heterocyclic ring, cycloalkylalkyl, (heterocyclic ring)carbonyl, optionally s
Aoki Yuhko
Ebiike Hirosato
Fujii Toshihiko
Kawasaki Ken'ichi
Liu Pingli
Basilea Pharmaceutica AG
Johnston George W.
Lambkin Deborah C.
Tramaloni Dennis P.
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