Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-09-28
2002-01-22
Kifle, Bruck (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
06340680
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides oxazinoquinolone 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 causative 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 chloro 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, including cytomegalovirus (CMV) infections.
U.S. Pat. No. 4,847,373 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-de1,4-benzoxazine or a pyrido (1,2,3-de)-1,4-benzothiazine derivative.
SUMMARY OF THE INVENTION
The present invention provides a compound of formula I,
wherein R
1
is C
1-6
alkyl, optionally substituted with —OH, —OC
1-4
alkyl or het;
wherein C
1-6
alkyl is optionally partially unsaturated;
wherein het is a radical of a five- or six-membered heterocyclic ring having one or two heteroatoms selected from the group consisting of oxygen, sulfur and N; or a pharmaceutically acceptable salt, racemate, solvate, tautomer, optical isomer or prodrug derivative thereof.
In another aspect, the present invention also provides:
a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient (the composition preferably comprises an effective antiviral amount of the compound or salt),
a method of treating or preventing a herpesviral infection, comprising administering to a mammal (e.g. a human) in need of such treatment, a compound of formula (I) or a pharmaceutically acceptable salt thereof,
a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in medical treatment (e.g. the treatment or prevention of a herpesviral infection),
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 (e.g. a human), and
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
For the purpose of the present invention, 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 thereof.
The compounds of the present invention are named according to the IUPAC or CAS nomenclature system.
The term “C
1-6
″, ” refers to an alkyl group having one to six carbon atoms such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, and their isomeric forms thereof.
A 5- or 6-membered heterocyclic ring includes pyridinyl, morpholinyl, thiomorpholinyl, piperazinyl, imidazolyl, or pyrrolyl.
Compounds of the present invention may be in a form of pharmaceutically acceptable salts.
“Pharmaceutically acceptable salts” refers to those salts which possess the biological effectiveness and properties of the parent compound and which are not biologically or otherwise undesirable.
Compounds of the invention may have a chiral center and be isolated in optically active and racemic forms. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, tautomeric, or stereoisomeric form, or mixture thereof.
Specific and preferred values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents
Specifically, C
1-6
alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, hexyl, or heptyl; het can be pyrrolidino, piperidino, morpholino, thiomorpholino, or piperazine.
A specific value for R
1
is C
1-6
alkyl, which may be partially unsaturated and is optionally substituted by hydroxy or het.
A specific value for R
1
is propyl.
A specific value for R
1
is 3-hydroxypropyl.
A specific value for R
1
is 3-hydroxy-1-propynyl.
A specific value for R
1
is 4-morpholinylmethyl.
Examples of the present invention are:
a. N-(4-Chlorobenzyl)-9-(4-morpholinylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
b. N-(4-Chlorobenzyl)-9-(3-hydroxy-1-propynyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
c. N-(4-Chlorobenzyl)-9-(3-hydroxypropyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide, or
d. N-(4-Chlorobenzyl)-7-oxo-9-propyl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide.
The following Charts A-B describe the preparation of the compounds of formula I of the present invention. All of the starting materials are prepared by procedures described in these charts, by procedures well known to one of ordinary skill in organic chemistry or can be obtained commercially. All of the final compounds of the present invention are prepared by procedures described in these charts or by procedures analogous thereto, which would be well known to one of ordinary skill in organic chemistry. All of the variables used in the charts are as defined below or as in the claims.
In Chart A, acid A-1,3-hydroxy-4-nitrobenzoic acid, is reacted with thionyl chloride to give the corresponding acid chloride, which is then treated with morpholine to provide amide A-2. Alkylation of the phenolic hydroxyl group is accomplished using methyl bromoacetate and potassium carbonate in refluxing acetone to give A-3. Reduction of the nitro group using hydrogen gas and catalytic palladium, f
Thaisrivongs Suvit
Turner Steven Ronald
Kifle Bruck
Pharmacia and Upjohn Company
Yang Lucy X.
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