Pyrroloquinolones as antiviral agents

Details Pyrroloquinolones as antiviral agents Pyrroloquinolones as antiviral agents

2001-06-22

2003-02-25

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S294000, C514S228200, C514S232500, C514S235800, C544S060000, C544S082000, C544S121000, C544S126000, C546S094000

Reexamination Certificate

active

06525049

ABSTRACT:

FIELD OF THE INVENTION
The present invention provides pyrroloquinolones that are useful as antiviral agents, more specifically, provides compounds of formula (I) described herein below against herpesviruses.
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 herpesviruses, 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 herpesviruses 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 causative 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 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
PCT publication WO 97/31000 discloses pyrroloquinolone carboxamides useful as antiviral agents.
PCT publication WO 97/30999 discloses pyrroloquinolones with bicyclic carboxamides useful as antiviral agents.
U.S. Pat. No. 3,917,609 discloses pyrroloquinoline carboxylic acid derivatives useful as antiviral agents.
U.S. Pat. No. 4,547,511 discloses heterocyclic carboxamides which increase the activity of the immune system.
U.S. Pat. No. 4,317,820 discloses &bgr;-lactam series compound useful as antibacterial agents.
U.S. Pat. No. 5,792,774 discloses quinolones and their therapeutic use.
PCT publication WO 91/05783 discloses heterocyclic compounds that are 5-HT
3
antagonists.
PCT publication WO 92/18483 discloses quinoline derivatives.
Abstract of Japanese patent J5 5145-612 discloses antimicrobial agent contains a novel &bgr;-lactam ring.
Abstract of Japanese patent J5 5153-792 discloses cephalosporanic derivatives.
GB 2 236 751 A discloses 4-oxo-quinolines which are 5-HT3 antagonists.
Blurton, et. al
Heterocycles,
1997, 45, 2395 discloses the preparation of pyrroloquinolones.
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:
R
1
is F, Cl, Br, CN or NO
2
;
R
2
and R
3
are independently H, halo, OR
11
, C(═O)R
7
, C(═O)OR
11
, C
3-8
cycloalkyl, C
1-7
alkyl which may be partially unsaturated and optionally substituted by one or more halo, C
3-8
cycloalkyl, R
12
, OR
14
, SR
11
, SR
14
, NR
8
R
9
, NR
11
C(O)R
7
, (C═O)C
1-7
alkyl, or SO
m
R
10
;
R
4
and R
5
are independently
(a) H,
(b) halo,
(c) aryl,
(d) S(O)
m
R
7
,
(e) (C═O)R
7
,
(i) (C═O)OR
10
,
(g) CN,
(h) het, wherein said het is bound via a carbon atom,
(i) OR
11
,
(j) Ohet,
(k) NR
8
R
9
(l) SR
11
,
(m) Shet,
(n) NHCOR
13
,
(o) NHSO
2
R
13
,
(p) C
3-8
cycloalkyl, or
(q) C
1-7
alkyl which may be partially unsaturated and optionally substituted by one or more R , OR
14
, SR
11
, SR
14
, NR
8
R
9
, halo, C
3-8
cycloalkyl, (C═O)C
1-7
alkyl, or SO
m
R
10
;
R
6
is H, halo, C
3-8
cycloalkyl, or C
1-4
alkyl optionally substituted by 1-3 halo;
R
7
is
(a) C
1-7
alkyl,
(b) C
3-8
cycloalkyl,
(c) NR
8
R
9
,
(d) aryl, or
(e) het, wherein said het is bonded via a carbon atom;
R
8
and R
9
are independently
(a) H,
(b) aryl,
(c) C
3-8
cycloalkyl,
(d) C
1-7
alkyl which may be partially unsaturated and is optionally substituted by one or more NR
11
R
11
, R
12
, SO
m
R
10
, CONR
11
R
11
, OH, aryl, het, C
3-8
cycloalkyl, or halo, or
(e) R
8
and R
9
together with the nitrogen to which they are attached for a het;
R
10
is
(a) aryl,
(b) het,
(c) C
3-8
cycloalkyl, or
(d) C
1-7
alkyl which may be partially unsaturated and is optionally substituted by one or more NR
11
R
11
, R
12
, SH, CONR
11
R
11
, C
3-8
cycloalkyl, or halo;
R
11
is
(a) H,
(b) C
3-8
cycloalkyl,
(c) C
1-7
alkyl optionally substituted by OH, or
(d) aryl;
R
12
is
(a) OR
11
,
(b) Ohet,
(c) Oaryl,
(d) CO
2
R
11
,
(e) het,
(f) aryl, or
(g) CN;
R
13
is
(a) H,
(b) het,
(c) aryl,
(d) C
3-8
cycloalkyl, or
(e) C
1-7
alkyl optionally substituted by NR
11
R
11
or R
12
;
R
14
is
(a) (P═O)(OR
15
)
2
,
(b) CO(CH
2
)
n
CON(CH
3
)—(CH
2
)
n
SO
3
−
M
+
,
(c) an amino acid,
(d) C(═O)aryl,
(e) C(═O)C
1-7
alkyl optionally substituted by NR
11
R
11
, aryl, het, CO
2
H, or O(CH
2
)
n
CO
2
R
15
;
R
15
is
(a) H, or
(b) C
1-7
alkyl;
aryl is a phenyl radical or an ortho-fused bicyclic carbocyclic radical wherein at least one ring is aromatic; at each occurrence, aryl may be additionally substituted with one or more halo, CN, CO
2
R
11
, SR
11
, OR
11
, NR
11
R
11
, C
1-4
alkyl, CF
3
, or C
3-8
cycloalkyl;
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, SO
m
, and NX; wherein X is H, C
1-4
alkyl or absence, wherein het is optionally fused to a benzene ring, or any bicyclic heterocycle group; at each occurrence, het may be additionally substituted with one or more halo, CN, CO
2
R
11
, COR
13
, SR
11
, OR
11
, NR
11
R
11
, C
1-4
alkyl, CF
3
, C
3-8
cycloalkyl, oxo or oxime;
at each occurrence, C
3-8
cycloalkyl may be partially unsaturated and optionally substituted by one or more R
12
, SR
11
, NR
11
R
11
, CONR
11
R
11
, or halo;
m is 0, 1, or 2; and
at each occurrence n is independently 1, 2, 3, 4, 5 or 6;
M is sodium, potassium, or lithium.
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 “prop

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