Oxazinoquinolones useful for the treatment of viral infections

Details Oxazinoquinolones useful for the treatment of viral infections Oxazinoquinolones useful for the treatment of viral infections

2001-06-28

2004-01-06

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S101000

Reexamination Certificate

active

06673793

ABSTRACT:

FIELD OF THE INVENTION
The present invention provides oxazinoquinolone and thioxazinoquinolone derivatives having a ring connecting position 4 (N-4) and position 11 (C-11), and more specifically, provides compounds of formula (I) described herein below. These compounds are useful as antiviral agents, in particular, as agents against viruses of the herpes family.
BACKGROUND OF THE INVENTION
The herpesviruses comprise a large family of double stranded DNA viruses. They are also a source of the most common viral illnesses in man. Eight of the herpes viruses, herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), human cytomegalovirus (HCMV), epstein-Barr virus (EBV), and human herpes viruses 6, 7, and 8 (HHV-6, HHV-7, and (HHV-8), have been shown to infect humans.
HSV-1 and HSV-2 cause herpetic lesions on the lips and genitals, respectively. They also occasionally cause infections of the eye and encephalitis. HCMV causes birth defects in infants and a variety of diseases in immunocompromised patients such as retinitis, pneumonia, and gastrointestinal disease. VZV is the causitive agent of chicken pox and shingles. EBV causes infectious mononucleosis. It can also cause lymphomas in immunocompromised patients and has been associated with Burkitt's lymphoma, nasopharyngeal carcinoma, and Hodgkins disease. HHV-6 is the causitive agent of roseola and may be associated with multiple sclerosis and chronic fatigue syndrome. HHV-7 disease association is unclear, but it may be involved in some cases of roseola. HHV-8 has been associated with Karposi's sarcoma, body cavity based lymphomas, and multiple myeloma.
Due to the unique position of the para-substitutent on the N-phenylmethyl of formula I described herein below, compounds of the present invention demonstrate unexpected activity against the above reference herpesviral infections, particularly, human cytomegaloviral infection.
INFORMATION DISCLOSURE
U.S. Pat. No. 5,792,774 discloses oxazino 1,4-dihydro-4-oxoquinolines useful for the treatment of a large number of diseases modulated by tissue necrosis factor (TNF) or phosphodiesterase IV, includng cytomegalovirus (CMV) infections.
U.S. Pat. No. 4,847,375 discloses 1,8-bridged 4-quinoline-3-carboxylic acids useful as antibacterial agents.
U.S. Pat. No. 5,583,135 discloses heterotricyclic derivatives having a strong immunomodulating activity, anti-inflammatory activity and anti-cancer activity.
The abstract of Japanese Patent JP 10324631-A discloses IgE antibody production inhibitor comprise a pyrido(1,2,3-del,4-benzoxazine or a pyrido (1,2,3,-de)-1,4-benzothiazine derivative.
PCT patent application, PCT/US00/21985 discloses oxazinoquinolones useful for the treatment of viral infections.
SUMMARY OF THE INVENTION
The present invention provides a compound of formula I,
or a pharmaceutically acceptable salt, racemate, solvate, tautomer, optical isomer or prodrug derivative thereof wherein:
each X is independently O or S;
Y is Cl, F, Br, CN or NO
2
;
R
1
, R
2
, R
3
and R
4
are independently
a) hydrogen,
b) N
3
,
c) CN,
d) fluoro,
e) trifluoromethyl,
f) aryl,
g) het,
h) C
1-8
alkyl, optionally substituted with R
6
or OR
7
, or
i) R
1
and R
2
or R
3
and R
4
together with the carbon to which they are attached form C
3-8
cycloalkyl or het;
R
5
is C
1-8
alkyl, which may be partially unsaturated and optionally substituted with one to three N
3
, halo, CN, R
6
or R
7
;
R
6
is
a) aryl,
b) het,
c) SO
i
R
8
,
d) OR
8
,
e) C(═O)OR
8
,
f) C(═O)R
8
, or
g) NR
8
R
9
;
R
7
is
a) P(═O)(OR
10
)
2
,
b) CO(CH
2
)
j
CON(CH
3
)(CH
2
)
k
SO
3
−
M
+
,
c) an amino acid,
d) C(═O)C
1-6
alkyl, optionally substituted by NR
10
R
10
, or
e) CO(CH
2
)
n
CO
2
H;
R
8
and R
9
are independently
a) hydrogen,
b) C
3-8
cycloalkyl,
c) aryl,
d) het, or
e) C
1-8
alkyl which is further optionally substituted with one or more aryl, het, halo, CN, CO
2
R
10
, SO
i
R
10
, OR
10
, NR
10
R
10
, CF
3
, or C
3-8
cycloalkyl;
R
10
is
a) H or
b) C
1-8
alkyl, optionally substituted with OH or OC
1-4
alkyl;
R
11
and R
12
are independently
a) hydrogen,
b) halo,
c) NO
2
,
d) CN,
e) R
6
,
f) SO
i
NR
8
R
9
, or
g) C
1-8
alkyl, which may be partially unsaturated and optionally substituted with one to three N
3
, halo, CN, R
6
or OR
7
;
aryl is
a phenyl radical, optionally fused with a saturated or unsaturated carbocyclic or heterocyclic ring; at each occurrence, aryl may be substituted with one or more halo, CN, CO
2
R
10
, SO
i
R
10
, OR
10
, NR
10
R
10
, CF
3
, C
3-8
cycloalkyl, or C
1-4
alkyl wherein C
1-4
alkyl is optionally substituted with OR
10
;
het is
a four-(4), five- (5), six- (6), or seven- (7) membered saturated or unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms selected from the group consisting of O, S, and NW, wherein W is hydrogen, C
1-4
alkyl, C(═O)OC
1-4
alkyl or absent, wherein het is optionally fused with a benzene ring, a carbcyclic or a heterocyclic ring; at each occurrence, het may be substituted with one or more halo, CN, CO
2
R
10
, SO
i
R
10
, OR
10
, NR
10
R
10
, C
1-4
alkyl, CF
3
, C
3-8
cycloalkyl, oxo or oxine;
at each occurrence, a cycloalkyl group may be substituted with C
1-4
alkyl, OR
10
, oxo, oxine, or a spiro fused het;
i is 0, 1 or 2;
j is 1, 2, 3, 4, 5, or 6;
k is 1, 2, 3, 4, 5, or 6;
n is 1, 2, 3, 4, 5, or 6;
M is sodium, potassium, or lithium; and
with the following provisos:
a) at least one of R
1
, R
2
, R
3
and R
4
is other than hydrogen;
b) where R
1
, R
2
, R
3
and R
4
are independently C
1-8
alkyl, at least one of the alkyl groups is substituted with R
6
or OR
7
.
The present invention further provides a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier (the composition preferably comprises an effective antiviral amount of the compound or salt).
The present invention further provides a method of treating or preventing a herpesviral infection, comprising administering to a mammal in need of such treatment, a compound of formula (I) or a pharmaceutically acceptable salt thereof.
The present invention further provides a method of treating or preventing a herpesviral infection comprising administering orally, parenterally, topically, rectally, nasally, sublingually or transdermally an effective amount of a compound of claim 1.
The present invention further provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in medical treatment.
The present invention further provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof to prepare a medicament for treating or preventing a herpesviral infection in a mammal.
The present invention further provides a method for inhibiting a viral DNA polymerase, comprising contacting (in vitro or in vivo) the polymerase with an effective inhibitory amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.
The invention also provides novel intermediates and processes disclosed herein that are useful for preparing compounds of formula I.
DETAILED DESCRIPTION OF THE INVENTION
The following definitions are used, unless otherwise described. Halo denotes fluoro, chloro, bromo, or iodo. Alkyl, alkoxy, etc. denote both straight and branched groups; but reference to an individual radical such as “propyl” embraces only the straight chain radical, a branched chain isomer such as “isopropyl” being specifically referred to. When alkyl can be partially unsaturated, the alkyl chain may comprise one or more (e.g. 1, 2, 3, or 4) double or triple bonds in the chain.
The carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix C
i-j
indicates a moiety of the integer “i” to the integer “j” carbon atoms, inclusive. Thus, for example, (C
1-3
)alkyl refers to alkyl of one to three carbon atoms, inclusive, or methyl, ethyl, propyl and isopropyl, straight and branched forms thereo

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